interacts_with DB08815?
Modulation of mucosal permeability by vasoactive intestinal peptide or lidocaine affects the adjustment of luminal hypotonicity in rat duodenum . AIMS : To examine whether modulation of paracellular solute permeability affects the capability of the duodenum to adjust luminal osmolality . METHODS : Proximal duodenum was perfused with a hypotonic NaCl solution and effects on paracellular permeability to (51)Cr- DB00974 , motility , anion secretion , net fluid flux and perfusate osmolality determined in anaesthetized rats in the absence and presence of the P35354 inhibitor parecoxib . Vasoactive intestinal peptide ( P01282 ) was used to reduce and lidocaine to augment the hypotonicity-induced increase in paracellular permeability . RESULTS : DB01174 hypotonicity slightly increased paracellular permeability in control animals . DB08439 induced motility , increased electrolyte and fluid secretion , potentiated the hypotonicity-induced rise in paracellular permeability and enhanced the capability to adjust luminal osmolality . P01282 , given to control animals stimulated electrolyte and fluid secretion and augmented the capability to adjust luminal osmolality . Administration of P01282 to parecoxib-treated animals increased secretion further , markedly reduced the hypotonicity-induced increase in permeability but did not change the osmolality-adjusting capability . DB01174 lidocaine potentiated the hypotonicity-induced increase in permeability , reduced the hypotonicity-induced net fluid absorption and the osmolality-adjusting capability was 50 % greater than in controls . DB00281 , given to parecoxib-treated animals potentiated the hypotonicity-induced increase in permeability , reduced the hypotonicity-induced net fluid absorption but did not change the osmolality-adjusting capability . CONCLUSIONS : Vasoactive intestinal peptide reduces the osmolality-adjusting capacity of the duodenum by inhibiting paracellular solute permeability but improves this capacity by stimulating active electrolyte and fluid secretion . In contrast , lidocaine improves the osmolality-adjusting capability by augmenting paracellular solute transport but depresses it by reducing the hypotonicity-induced net fluid absorption . Anatomical specificity in the modulation of activity-regulated genes after acute or chronic lurasidone treatment . DB08815 is a novel second generation antipsychotic drug characterized by a multi-receptor profile . Besides the high affinity for 5- Q13049 and D2 receptors , it is also characterized by potent P34969 receptor antagonism , which may be beneficial for mood and cognition . Considering that dose-dependent changes in receptor occupancy may differentially impact gene transcription , we aimed at investigating the effects of acute and chronic treatments with different doses of lurasidone ( 1 , 3 and 10mg/kg ) in rats on the expression of the activity-regulated genes Arc , Zif268 and Npas4 , which are markers of neuronal activation and are also associated with neuroadaptive mechanisms . Our results show dose-dependent and anatomically-selective differences after acute and chronic lurasidone treatment . Indeed , the effects produced by acute treatment seem to reflect the modulatory activity of lurasidone at selected neurotransmitter receptors . In fact , low doses of the drug acted in the hippocampus , while high doses acted in the striatum , reflecting the high predominance of D2 receptor expression in this brain region . On the contrary , chronic treatment with lurasidone revealed a different profile of IEGs modulation , possibly reflecting neuroadaptive changes set in motion in response to repetitive drug exposure . In summary , the multi-receptor profile of lurasidone leads to the recruitment of different brain structures in a dose-related manner and this may be important for its therapeutic properties , particularly with respect to antidepressant activity and cognition . Antitumor activity of lenvatinib ( e7080 ) : an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models . Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor ( P15692 ) signaling pathway is a promising therapeutic strategy for thyroid cancer . DB09078 mesilate ( lenvatinib ) is a potent inhibitor of P15692 receptors ( P17948 -3 ) and other prooncogenic and prooncogenic receptor tyrosine kinases , including fibroblast growth factor receptors ( P11362 -4 ) , platelet derived growth factor receptor α ( PDGFRα ) , P10721 , and P07949 . We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice . Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer ( DTC ) , 5 anaplastic thyroid cancer ( ATC ) , and 1 medullary thyroid cancer ( P04629 ) xenograft models . DB09078 also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts , while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines : that is , RO82-W-1 and TT cells . Western blot analysis showed that cultured RO82-W-1 cells overexpressed P11362 and that lenvatinib inhibited the phosphorylation of P11362 and its downstream effector Q8WU20 . DB09078 also inhibited the phosphorylation of P07949 with the activated mutation C634W in TT cells . These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and P07949 signaling pathway in preclinical human thyroid cancer models . Structural differences between Pb2+- and Ca2+-binding sites in proteins : implications with respect to toxicity . Pb(2+) is known to displace physiologically-relevant metal ions in proteins . To investigate potential relationships between Pb(2+)/protein complexes and toxicity , data from the protein data bank were analyzed to compare structural properties of Pb(2+)- and Ca(2+)-binding sites . Results of this analysis reveal that the majority of Pb(2+) sites ( 77.1 % ) involve 2-5 binding ligands , compared with 6+/-2 for non-EF-Hand and 7+/-1 for EF-Hand Ca(2+)-binding sites . The mean net negative charge by site ( 1.7 ) fell between values noted for non-EF-Hand ( 1+/-1 ) and EF-Hand ( 3+/-1 ) . DB09140 is the dominant ligand for both Pb(2+) and Ca(2+) , but Pb(2+) binds predominantly with sidechain DB00142 ( 38.4 % ) , which is less prevalent in both non-EF-Hand ( 10.4 % ) and EF-Hand ( 26.6 % ) Ca(2+)-binding sites . A comparison of binding geometries where Pb(2+) has replaced Ca(2+) in calmodulin ( P62158 ) and Zn(2+) in 5-aminolaevulinic acid dehydratase ( P13716 ) revealed protein structural changes that appear to be unrelated to ionic displacement . Structural changes observed with P62158 may be related to opportunistic binding of Pb(2+) in regions of high electrostatic charge , whereas P13716 may bind multiple Pb(2+) ions in the active site . These results suggest that Pb(2+) adapts to structurally-diverse binding geometries and that opportunistic binding may play an active role in molecular metal toxicity . Ameliorative Effect of a Selective Endothelin P25101 Receptor Antagonist in Rat Model of L- DB00134 -induced Vascular Dementia . The present study was designed to investigate the efficacy of selective P25101 receptor antagonist , ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia . L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats . DB06403 was administered to L-methionine-treated effect rats for 4 weeks ( starting from 5(th) to 8(th) week of L-methionine treatment ) . On 52(nd) day onward , the animals were exposed to the Morris water maze ( MWM ) for testing their learning and memory abilities . Vascular endothelial function , serum nitrite/nitrate levels , brain thiobarbituric acid reactive species ( TBARS ) , brain reduced glutathione ( DB00143 ) levels , and brain acetylcholinesterase ( P22303 ) activity were also measured . L-methionine-treated animals showed significant learning and memory impairment , endothelial dysfunction , decrease in/serum nitrite/nitrate and brain DB00143 levels along with an increase in brain TBARS levels and P22303 activity . DB06403 significantly improved hyperhomocysteinemia-induced impairment of learning , memory , endothelial dysfunction , and changes in various biochemical parameters . These effects were comparable to that of donepezil serving as positive control . It is concluded that ambrisentan , a selective P25101 receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia . Interactions between genetic variants of folate metabolism genes and lifestyle affect plasma homocysteine concentrations in the Boston Puerto Rican population . OBJECTIVE : To investigate genetic and lifestyle factors and their interactions on plasma homocysteine ( Hcy ) concentrations in the Boston Puerto Rican population . DESIGN : Cross-sectional study . Plasma concentrations of Hcy , folate , vitamin B12 and pyridoxal phosphate were measured , and genetic polymorphisms were determined . Data on lifestyle factors were collected in interviews . SETTING : A population survey of health and nutritional measures . SUBJECTS : A total of 994 Puerto Rican men and women residing in the Boston metropolitan area . RESULTS : Smoking status was positively associated with plasma Hcy . Genetic polymorphisms P42898 677C→T , Q04609 1561C→T , Q04609 rs647370 and Q96NT5 928A→G interacted significantly with smoking for Hcy . P42898 1298A→C ( P = 0·040 ) and Q96NT5 928A→G ( P = 0·002 ) displayed significant interactions with alcohol intake in determining plasma Hcy . Subjects with Q96NT5 928GG genotype had significantly higher plasma Hcy concentrations compared with carriers of the A allele ( AA+AG ; P = 0·030 ) among non-drinking subjects . When consuming alcohol , GG subjects had lower plasma Hcy levels compared with AA+AG subjects . Physical activity interacted significantly with Q99707 2756A→G in determining plasma Hcy ( P for interaction = 0·002 ) . Smoking interacted with physical activity for plasma Hcy ( P for interaction = 0·023 ) . CONCLUSIONS : Smoking and drinking were associated plasma Hcy concentrations . Genetic variants involved in folate metabolism further modify the effects of lifestyle on plasma Hcy . Dynamic but not constitutive association of calmodulin with rat Q9H1D0 channels enables fine tuning of Ca2+-dependent inactivation . The Ca(2+)-selective Q9H1D0 as well as the L-type Ca(2+) channel are regulated by the Ca(2+)-binding protein calmodulin ( P62158 ) . Here , we investigated the interaction of P62158 with rat (r) Q9H1D0 in response to alterations of intracellular Ca(2+) , employing Ca(2+)-imaging and patch-clamp techniques . Additionally , confocal Förster resonance energy transfer ( FRET ) microscopy on living cells was utilized as a key method to visualize in vivo protein-protein interactions essential for P62158 regulation of rTRPV6 activity . The effects of overexpressed P62158 or its Ca(2+)-insensitive mutant ( P62158 ( P22033 ) ) was probed on various rTRPV6 mutants and fragments in an attempt to elucidate the molecular mechanism of Ca(2+)/ P62158 -dependent regulation and to pinpoint the physiologically relevant rTRPV6- P62158 interaction site . A significant reduction of rTRPV6 activity , as well as an increase in current inactivation , were observed when P62158 was overexpressed in addition to endogenous P62158 . The Ca(2+)-insensitive P62158 ( P22033 ) , however , failed to affect rTRPV6-derived currents . Accordingly , live cell confocal FRET microscopy revealed a robust interaction for P62158 but not P62158 ( P22033 ) with rTRPV6 , suggesting a strict Ca(2+) dependence for their association . Indeed , interaction of rTRPV6 or its C terminus with P62158 increased with rising intracellular Ca(2+) levels , as observed by dynamic FRET measurements . An rTRPV6Delta(695-727) mutant with the very C-terminal end deleted , yielded Ca(2+) currents with a markedly reduced inactivation in accordance with a lack of P62158 interaction as substantiated by FRET microscopy . These results , in contrast with those for P62158 -dependent L-type Ca(2+) channel inactivation , demonstrate a dynamic association of P62158 with the very C-terminal end of rTRPV6 ( aa 695-727 ) , and this enables acceleration of the rate of rTRPV6 current inactivation with increasing intracellular P62158 concentrations . Suppression of 3-deoxyglucosone and heparin-binding epidermal growth factor-like growth factor mRNA expression by an aldose reductase inhibitor in rat vascular smooth muscle cells . Reactive carbonyl compounds and oxidative stress have been recently shown to up-regulate the expression of heparin-binding epidermal growth factor-like growth factor ( HB- P01133 ) , a potent mitogen for vascular smooth muscle cells ( SMCs ) produced by SMC themselves . Because the polyol pathway has been reported to influence the formation of carbonyl compounds and the oxidative stress in various cells , we conducted this study to investigate whether the polyol pathway affects HB- P01133 expression along with the generation of carbonyl compounds and the oxidative stress in SMCs . We found that , compared with those cultured with 5.5mM glucose , SMCs cultured with 40 mM glucose showed the accelerated thymidine incorporation , elevated levels of intracellular sorbitol , 3-deoxyglucosone ( 3-DG ) , advanced glycation end products ( AGEs ) , and thiobarbituric acid-reactive substances ( TBARS ) along with the enhanced expression of HB- P01133 mRNA . An aldose reductase inhibitor ( Q9Y4X5 ) , Q9NYY3 -860 , significantly inhibited all of these abnormalities , while aminoguanidine suppressed 3-DG levels and HB- P01133 mRNA expression independent of sorbitol levels . The results suggest that the polyol pathway may play a substantial role in SMC hyperplasia under hyperglycemic condition in part by affecting HB- P01133 mRNA expression via the production of carbonyl compounds and oxidative stress . Silencing of ALA dehydratase affects ALA-photodynamic therapy efficacy in K562 erythroleukemic cells . Synthesis of protoporphyrin IX ( PpIX ) by malignant cells is essential for the success of ALA-based photodynamic therapy ( PDT ) . Two key enzymes that were described as affecting PpIX accumulation during ALA treatment are porphobilinogen deaminase ( P08397 ) and ferrochelatase . Here , we show that down regulation of ALA dehydratase ( P13716 ) expression and activity by specific shRNA induced a marked decrease in PpIX synthesis in K562 erythroleukemic cells . Photo-inactivation efficacy following DB00855 was directly correlated with P13716 -silencing and cellular levels of PpIX . MTT metabolism following DB00855 was shown to be 60 % higher in P13716 -silenced cells in comparison to control cells , indicating that mitochondria were protected in the silenced cells . Morphological analysis by scanning electron microscopy ( SEM ) of cells treated by DB00855 showed no morphological changes in P13716 -silenced cells , in contrast to controls exhibiting cell deformations and lysis . Membrane integrity following DB00855 was kept intact and undamaged in P13716 -silenced cells as examined by P08758 -FITC/PI staining and LDH-L leakage . We conclude that P13716 , although it is present in the cell at abundant levels , has a major and limiting role in regulating PpIX synthesis and DB00855 outcome . AM2389 , a high-affinity , in vivo potent P21554 -receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 (®) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB(1)R ) HHC-ligand AM2389 [ 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251 , a CB(1)R-selective antagonist/inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg/kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin/water . Generalization/substitution tests were conducted with AM2389 , AM5983 , and Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . RESULTS : Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg/kg ) . AM251 ( 3 and 10 mg/kg ) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025 , 0.0571 , and 0.2635 mg/kg , respectively , in the low-dose condition . The corresponding ED(50) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg/kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation . delta- DB00855 dehydratase ( P13716 ) porphyria : the first case in North America with two novel P13716 mutations . The molecular basis of the enzymatic defect responsible for delta-aminolevulinate dehydratase ( P13716 ) porphyria ( ADP ) was investigated in a 14-year-old male who presented clinical and laboratory findings typical of ADP . Nucleotide sequence analysis of P13716 cDNAs from the proband revealed two novel mutations , a 265G to A base transition ( C1 ) and a 394C to T base transition ( P06681 ) , resulting in amino acid substitutions , Glu89Lys and Cys132Arg , respectively . Both mutations were present within exon 5 of the P13716 gene , and appeared to influence the binding of zinc to the enzyme which is essential for enzyme activity . It was found that the C1 mutation was inherited from his father , while the P06681 mutation was from his mother . Expression of these mutant P13716 cDNAs in Chinese hamster ovary cells produced normal P13716 mRNA levels , but markedly decreased P13716 protein and enzyme activity . These results suggest that the combination of the two aberrant ALADs with little enzyme activity accounts for the markedly decreased P13716 activity observed in the proband . This case represents the molecular analysis of the P13716 gene defects in the first case of ADP identified in North America , who is a compound heterozygote for two novel P13716 gene defects . Role of protein kinase C in agonist-induced desensitization of 5-HT₁A receptor coupling to calcium channels in P03951 cells . The 5-Hydroxytriptamine 1A receptor ( P08908 ) is expressed both as a pre- and post-synaptic receptor in neurons . The presynaptic receptor preferentially desensitizes compared to post-synaptic receptors , suggesting different underlying mechanisms of agonist-induced desensitization . Using P03951 cells as a model of post-synaptic neurons , the present study examined the role of protein kinase C ( PKC ) and protein kinase A ( PKA ) in desensitization of the P08908 -receptor by agonist . Desensitization in whole cell experiments was dependent on internal [ Ca(2+) ] and was blocked by chelation of intracellular Ca(2+) . Using the perforated patch technique , desensitization was reduced when Ba(2+) was used as the conducting cation . Selective inhibitors of conventional PKC isoforms prevented 5-HT-induced desensitization , whereas an inhibitor of PKA did not . In cells in which 3 PKC/PKA sites located in the third intracellular loop ( i3 ) of the P08908 receptor were mutated ( i3 , T229A-S253G-T343A ) , 5-HT-mediated desensitization was reduced ( and abolished in the absence of intracellular Ca(2+) ) . In cells in which a fourth mutation was added ( T149 in the second i2 loop ) , the cells responded similarly to the triple mutants suggesting that phosphorylation of T149 does not contribute greatly to the desensitization induced by 5-HT-mediated activation of PKC . Thus agonist-induced uncoupling of the P08908 -receptor is PKC-dependent , but requires a different set of phosphorylation sites than phorbol ester-mediated PKC activation , suggesting differential recruitment of PKC . Furthermore , these studies reveal that P08908 -receptor desensitization utilizes a different kinase in P03951 cells and serotonergic neurons , which may in part account for their differential sensitivity in vivo . [ A molecular study of methylmalonic aciduria : structure-function correlations ] . Cobalamin ( DB00115 ) non-responsive methylmalonic acidemia is caused by mutations in the P22033 locus on chromosome 6p21 encoding the enzyme methylmalonyl DB01992 mutase ( EC 5.4.99.2 ) . This disorder has been extensively studied by biochemical , somatic cell genetic and molecular techniques . Mutations have been identified which cause classic mut(o) phenotypes in which there is no detectable enzymatic activity , as well as mut- phenotypes in which there is residual cobalamin-dependent activity . Mutations which exhibit interallelic complementation have been identified within both of these groups . These mutations illustrate the position , structure , and function of critical domains within this cobalamin binding enzyme and provide new insights into the biochemical and clinical consequences of enzyme deficiency . The homology of the cobalamin binding region has allowed mutations of the mutase to be mapped onto the x-ray structure of methionine synthase ( EC 2.1.1.13 ) . Direct comparison of fluorescence- and bioluminescence-based resonance energy transfer methods for real-time monitoring of thrombin-catalysed proteolytic cleavage . In this study , a representative FRET system ( P27918 donor and YFP acceptor ) is compared with the BRET(2) system ( Renilla luciferase donor , green fluorescent protein(2) ( GFP(2) ) acceptor and coelenterazine 400a substrate ) . Cleavage of a thrombin-protease-sensitive peptide sequence inserted between the donor and acceptor proteins was detected by the P07949 signal . Complete cleavage by thrombin changed the BRET(2) signal by a factor of 28.9+/-0.2 ( R.S.D. ( relative standard deviation ) , n=3 ) and the FRET signal by a factor of 3.2+/-0.1 ( R.S.D. , n=3 ) . The BRET(2) technique was 50 times more sensitive than the FRET technique for monitoring thrombin concentrations . Detection limits ( blank signal+3sigma(b) , where sigma(b)=the standard deviation ( S.D. ) of the blank signal ) were calculated to be 3.05 and 0.22nM thrombin for FRET and BRET(2) , respectively . This direct comparison suggests that the BRET(2) technique is more suitable than FRET for use in proximity assays such as protease cleavage assays or protein-protein interaction assays . Effect of selective inhibition of cyclooxygenase-2 on lipopolysaccharide-induced hyperalgesia . Lipopolysaccharide ( LPS ) is known to increase the expression and release of various pro-inflammatory mediators , including cyclooxygenase-2 ( P35354 ) and produce hyperalgesia . It is also well known that prostaglandins ( PGs ) , synthesised both in the periphery and centrally by P36551 isoforms , play a key role in sensitisation of nociceptors and nociceptive processing . To investigate the role of P35354 in LPS-induced hyperalgesia , parecoxib , a selective P35354 -inhibiting pro-drug , was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS ( 50 microg/mouse or 25 microg/paw of rat , respectively ) . DB03166 -induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of P35354 on LPSinduced hyperalgesia . Animals showed significant hyperalgesic behavior 8 h after LPS injection . DB08439 ( up to 20 mg/kg , i.v. ) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS-pretreated mice . Similarly , parecoxib reversed the hyperalgesia in the LPS-injected paw but not in the contralateral paw of rats . Pre-treatment with dexamethasone , an inhibitor of P35354 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats . These findings suggest that inducible P35354 derived PGs are involved in central nociceptive processing , which resulted in hyperalgesic behavior following LPS administration and inhibition of P35354 or its expression attenuated LPS-induced hyperalgesia . A mechanism for the synergistic antimalarial action of atovaquone and proguanil . A combination of atovaquone and proguanil has been found to be quite effective in treating malaria , with little evidence of the emergence of resistance when atovaquone was used as a single agent . We have examined possible mechanisms for the synergy between these two drugs . While proguanil by itself had no effect on electron transport or mitochondrial membrane potential ( DeltaPsim ) , it significantly enhanced the ability of atovaquone to collapse DeltaPsim when used in combination . This enhancement was observed at pharmacologically achievable doses . DB01131 acted as a biguanide rather than as its metabolite cycloguanil ( a parasite dihydrofolate reductase [ P00374 ] inhibitor ) to enhance the atovaquone effect ; another P00374 inhibitor , pyrimethamine , also had no enhancing effect . DB01131 -mediated enhancement was specific for atovaquone , since the effects of other mitochondrial electron transport inhibitors , such as myxothiazole and antimycin , were not altered by inclusion of proguanil . Surprisingly , proguanil did not enhance the ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites . These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses DeltaPsim in malaria parasites . This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance . The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner . Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h P28221 receptors . 1. The release of glutamic acid and its modulation by 5-hydroxytryptamine ( 5-HT ) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours . 2 . The Ca2+-dependent K+ ( 15 mM ) -evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner ( EC50 = 2.9 nM ; maximal effect approximately 50 % ) . The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin . The P28222 / P28221 receptor agonist sumatriptan mimicked 5-HT ( EC50 = 6.4 nM ; maximal effect approximately 50 % ) ; the effect of sumatriptan was also methiothepin-sensitive . Selective P08908 receptor antagonists could not prevent the inhibition of glutamate release by 5-HT . 3 . The P28222 / P28221 receptor ligand GR 127935 and the P28335 / P28222 / P28221 receptor ligand metergoline were unable to prevent the 5-HT effect ; instead they inhibited glutamate release , their effects being abolished by methiothepin . Some P08908 receptor antagonists also displayed intrinsic agonist activity . 4 . The effect of sumatriptan was prevented by ketanserin , a drug known to display much higher affinity for recombinant h P28221 than for h P28222 receptors . 5 . We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h P28221 subtype . Association of folate with hearing is dependent on the 5,10-methylenetetrahdyrofolate reductase 677C --> T mutation . Vascular disease and its risk factors have been associated with the age-related hearing loss . We examined the association of elevated plasma homocysteine and its determinants with hearing levels . Pure-tone air conduction thresholds in 728 individuals with sensorineural hearing loss were not associated with homocysteine , erythrocyte folate and DB00165 . Low concentrations of serum folate and DB00115 were associated with better hearing . When folate status was below the median , 5,10-methylenetetrahydrofolate reductase ( P42898 ) 677TT homozygotes had similar hearing levels to subjects with a C allele . However , when folate status was above the median , P42898 677TT homozygotes had on an average 5 dB ( p = 0.037 ) and 2.6 dB ( p = 0.021 ) lower P03951 -high and P03951 -low hearing thresholds , respectively , than the subjects with a 677C allele . The relationship between serum folate and hearing thresholds appeared to be dependent on P42898 677 genotype ( CC , r = 0.13 , p = 0.034 ; TT , r = -0.10 , p = 0.291 ) . This supports the hypothesis that a greater one-carbon moiety commitment to de novo synthesis of nucleotides and an increase in formyl-folate derivatives relative to methyl-folate derivatives is protective for hearing . DB06403 for pulmonary arterial hypertension . Endothelin receptor antagonists ( ERAs ) are an important class of agents used for the treatment of pulmonary arterial hypertension ( PAH ) . DB06403 is an oral , once-daily , endothelin type-A receptor ( P25101 ) -selective , propanoic acid class ERA under clinical investigation for the treatment of PAH . In a Phase II study , ambrisentan improved 6-minute walk distance , Borg dyspnea index , World Health Organization Functional Class , and hemodynamics . DB06403 was well tolerated and adverse events were not dose related , including a low incidence and severity of liver function test abnormalities . There are no relevant interactions between ambrisentan and cytochrome P450 isoenzymes ( metabolism , induction or inhibition ) that might alter the activity of P450-metabolized drugs . Potential benefits of ambrisentan include oral , once-daily dosing , ET(A)-receptor selectivity , and the decreased risks of liver toxicity and adverse drug-drug interactions compared with other ERAs . Evaluation of an aldose reductase inhibitor on lens metabolism , ATPases and antioxidative defense in streptozotocin-diabetic rats : an intervention study . AIMS/HYPOTHESIS : P15121 inhibitors ( ARIs ) prevent biochemical abnormalities associated with diabetic complications . We evaluated whether a short-term intervention with an adequate dose of Q9Y4X5 , introduced at the very early , precataractous stage , reversed diabetes-induced metabolic imbalances , down-regulation of ATPases and oxidative stress in the lens . Methods . The groups included mature control and streptozotocin-diabetic rats treated with or without Q9Y4X5 sorbinil ( 65 mg x kg(-1) x day(-1) , in the diet , for 2 weeks after 4 weeks of untreated diabetes ) . Free cytosolic NAD+: DB00157 and NADP+:NADPH ratios were calculated from the lactate dehydrogenase and malic enzyme systems . Concentrations of metabolites and adenine nucleotides , Na+/K+-ATPase , H+-ATPase and Ca++-independent Mg++-ATPase activities and variables of oxidative stress were measured in individual lenses . Results . DB02712 treatment essentially corrected diabetes-induced sorbitol and fructose accumulation , myo-inositol depletion , decrease in free cytosolic NAD+: DB00157 ratio and energy deficiency . Malondialdehyde accumulation , reduced glutathione depletion and the increase in oxidized glutathione:reduced glutathione ratio were partially corrected . Free cytosolic NADP+:NADPH ratio and 4-hydroxyalkenal concentrations were similarly increased in diabetic rats treated with or without Q9Y4X5 . DB02712 did not counteract diabetes-induced down-regulation of the three ATPase activities . CONCLUSION/INTERPRETATION : All biochemical changes assessed in our study are known to be prevented by ARIs . Despite the essential normalization of the sorbitol pathway activity , only part of them were , however , reversed by the Q9Y4X5 treatment introduced at the very early , i.e. precataractous , stage of diabetes . Therefore , intervention studies can easily underestimate the importance of aldose reductase in the pathogenesis of diabetic complications and should be interpreted with caution . Arsenic decreases antinociceptive activity of paracetamol : possible involvement of serotonergic and endocannabinoid receptors . We assessed whether repeated arsenic exposure can decrease paracetamol-mediated antinociception by modulating serotonergic and endocannabinoid pathways . Rats were preexposed to elemental arsenic ( 4ppm ) as sodium arsenite through drinking water for 28 days . Next day paracetamol 's ( 400mg/kg , oral ) antinociceptive activity was assessed through formalin-induced nociception . Serotonin content and gene expression of P08908 , 5- Q13049 and P21554 receptors were evaluated in brainstem and frontal cortex . Arsenic decreased paracetamol-mediated analgesia . DB00316 , but not arsenic , increased serotonin content in these regions . Arsenic attenuated paracetamol-mediated increase in serotonin level . DB00316 did not alter P08908 expression , but caused down-regulation of 5- Q13049 and up-regulation of P21554 receptors . Arsenic down-regulated these receptors . However , paracetamol-mediated down-regulation of 5- Q13049 was more pronounced . Arsenic did not modify paracetamol 's effect on P08908 expression , but reduced paracetamol-mediated down-regulation of 5- Q13049 and reversed up-regulation of P21554 receptors . Results suggest arsenic reduced paracetamol-induced analgesia possibly by interfering with pronociceptive 5- Q13049 and antinociceptive P21554 receptors . P08908 and P34969 receptors contribute to lurasidone-induced dopamine efflux . DB08815 is a novel , atypical antipsychotic drug with serotonin [ 5-hydroxytryptamine ( 5-HT ) ] 2A , P34969 , dopamine ( DA ) D2 antagonist , and P08908 receptor partial agonist properties . The ability of lurasidone to reverse the effects of subchronic administration phencyclidine , to impair novel object recognition in rats , an animal model of cognitive impairment in schizophrenia , is dependent , in part , on its P08908 agonist and P34969 receptor antagonist properties . We tested whether P08908 partial agonism or P34969 antagonism , or both , contributed to the ability of lurasidone to enhance cortical and hippocampal DA efflux , which may be related to its ability to improve cognition . Here , we report that lurasidone , 0.25 and 0.5 , but not 0.1 mg/kg , subcutaneously , significantly increased DA efflux in the prefrontal cortex and hippocampus in a dose-dependent manner . DB08815 , 0.5 mg/kg , also produced a smaller increase in DA efflux in the nucleus accumbens . Pretreatment with the P08908 receptor antagonist , WAY100635 ( 0.2 mg/kg , subcutaneously ) , partially blocked the lurasidone-induced cortical and hippocampal DA efflux . Further , subeffective doses of the P08908 receptor agonist , tandospirone ( 0.2 mg/kg ) , or the P34969 antagonist , SB269970 ( 0.3 mg/kg ) , potentiated the ability of a subeffective dose of lurasidone ( 0.1 mg/kg ) to increase DA efflux in the prefrontal cortex . These findings suggest that the effects of lurasidone on the prefrontal cortex and hippocampus , DA efflux are dependent , at least partially , on its P08908 agonist and P34969 antagonist properties and may contribute to its efficacy to reverse the effects of subchronic phencyclidine treatment and improve schizophrenia . Effects of lurasidone on executive function in common marmosets . Cognitive impairment is one of the major symptoms of schizophrenia , and is considered largely due to dysfunctions in the prefrontal cortex ( P27918 ) . DB08815 , a novel atypical antipsychotic agent with high binding affinity for dopamine D2 , serotonin P34969 , 5- Q13049 and P08908 receptors has been reported to have superior efficacy in rodents ' models of cognitive impairment . However , the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non-human primates . In this study , we investigated the effect of lurasidone on executive function , which is one of the cognitive domains , in common marmosets and compared the results to those of other antipsychotics . The effects of lurasidone , haloperidol , olanzapine , risperidone , quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours ( ORD ) task . Before drug treatment , marmosets ' success rates in the easy trial of the test were almost 90 % . However , maximum success in the difficult trial of the task reached only 50 % after 8 days of training . DB00502 , olanzapine and risperidone decreased correct performance even in the easy trial of the task . All drugs , except lurasidone , impaired success rate in the difficult trial . On the other hand , lurasidone dose-dependently increased marmosets ' success rates in the difficult trial with significant effect at 10mg/kg . In conclusion , we have shown in this study that lurasidone , unlike conventional antipsychotics , improves cognition associated with executive function in common marmosets . These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics . Safety and efficacy evaluation of ambrisentan in pulmonary hypertension . INTRODUCTION : Pulmonary arterial hypertension ( PAH ) is characterized by an increase in pulmonary vascular resistance , which can lead to right heart failure and death . P05305 binding P25101 and ETB receptors seem to play a critical role in the pathogenesis and progression of the disease , and oral endothelin receptor antagonists ( ERAs ) have been shown to be an effective treatment . DB00559 and P25101 -selective ambrisentan are the ERAs currently available for PAH treatment . AREAS COVERED : On the basis of the analysis of the literature , this paper addresses the efficacy and safety of ambrisentan in the treatment for PAH . EXPERT OPINION : DB06403 has shown an efficacy comparable with other ERAs . Compared with DB00559 , ambrisentan seems to have a better safety profile with regards to hepatic safety and drug-drug interactions . On the other hand , ambrisentan shows a higher rate of other adverse events , such as nasal congestion and peripheral edema . DB06403 is a viable option for PAH treatment . However , there is still a need for more robust data about long-term mortality , treatment in non-PAH pulmonary hypertension ( PH ) ( such as PH due to left heart disease and PH due to chronic hypoxic lung diseases ) and combination therapy . P11362 - 5-hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5-hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co-immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) -5-hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing P09038 levels . Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8-OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5-HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling . Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 -Flk-1-pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 /Flt-1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt-1 receptor antagonizing peptides , we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt-1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt-1 in vitro . In vivo , F56 fused with P00374 ( P00374 -F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 -F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 -F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR-H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt-1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt-1 . Thus , short peptide F56 may have clinical potential in tumor therapy . Agonist-induced glycogenolysis in rabbit retinal slices and cultures . 1. The effects of different putative retinal transmitters and/or modulators on glycogenolysis in rabbit retinal slices and in retinal Müller cell cultures were examined . 2 . Incubation of rabbit retinal slices or primary retinal cultures ( either 3-5 day-old or 25-30 day-old ) in a buffer solution containing [ 3H ] -glucose resulted in the accumulation of newly synthesized [ 3H ] -glycogen . 3 . DB00368 ( NA ) , isoprenaline , vasoactive intestinal peptide ( P01282 ) , 5-hydroxytryptamine ( 5-HT ) and 8-hydroxy-dipropylaminetetralin ( 8-OH-DPAT ) stimulated the hydrolysis of this newly formed 3H-polymer . The potency order of maximal stimulations was : P01282 greater than NA greater than isoprenaline greater than 5-HT greater than 8-OH-DPAT . 4 . The putative retinal transmitters , dopamine , gamma-aminobutyric acid ( GABA ) , glycine and taurine and the muscarinic agonist carbachol ( CCh ) had no effect on [ 3H ] -glycogen content . 5 . The glycogenolytic effects of NA/isoprenaline and 5-HT/8-OH-DPAT appear to be mediated by beta-adrenoceptors and 5-HT1 receptors ( possibly P08908 ) , respectively while the P01282 -induced response involved another receptor subtype . 6 . Agonists which mediated [ 3H ] -glycogen hydrolysis also stimulated an increase in adenosine 3':5'-cyclic monophosphate ( cyclic AMP ) formation . Both responses are blocked to a similar extent by the same antagonists and so are probably mediated via the same receptor subtypes . Moreover , dibutyryl cyclic AMP ( db cyclic AMP ) promoted tritiated glycogen breakdown in the three retinal preparations . 7 . Not all receptors linked to cyclic AMP production however promote glycogenolysis . Dopamine and apomorphine stimulated cyclic AMP formation via D1-receptors without influencing glycogenolysis . These receptors are exclusively associated with neurones . Inhibition of the trigemino-vascular system with P28221 agonist drugs : selectively targeting additional sites of action . Inappropriate activation of the trigemino-vascular system is thought to be important in the pathogenesis of a migraine attack . The P28221 agonist sumatriptan , which is highly effective in the acute treatment of migraine , inhibits trigemino-vascular activation in animals , although its actions are normally limited to peripheral components of the trigemino-vascular system . DB00315 , a novel P28221 agonist drug , which is also highly effective in the acute treatment of migraine , acts not only at these sites , but , additionally within the brainstem , inhibiting trigemino-vascular activation centrally as well as peripherally . This article describes the pre-clinical development of DB00315 and considers , specifically , the approaches taken in the design of a molecule with attributes which facilitate access to brainstem components of the trigeminal pathway and combine this with good oral bioavailability . Identification and characterization of two enzymes involved in the intracellular metabolism of cobalamin . DB00115 beta-ligand transferase and microsomal cob(III)alamin reductase . Two enzymes involved in the intracellular metabolism of cobalamin have been identified and characterized : cyanocobalamin beta-ligand transferase and microsomal cob(III)alamin reductase . The beta-ligand transferase is a cytosolic enzyme utilizing DB03147 , NADPH and reduced glutathione . The product of the reaction has been identified as glutathionyl-cobalamin . DB00157 -linked cob(III)alamin reductase has been found in two subcellular fractions : microsomal and inner mitochondrial membrane . The product of the reduction catalyzed by the microsomal enzyme has been identified as cob(II)alamin . In cbl C mutant fibroblasts , the specific activities of cyanocobalamin beta-ligand transferase and cob(III)alamin reductase were markedly decreased and have varied from 3 % -30 % and 36 % -42 % of normal , respectively . The specific activity of mitochondrial cob(III)alamin reductase was only 30 % of normal in two cbl C mutants and normal in remaining mutant cell lines . In the cbl D cells , the specific activities were 33 % and 55 % . Mitochondrial cob(III)alamin reductase was not affected by cbl D mutation . Q99707 , L-methylmalonyl- DB01992 mutase and microsomal cytochrome c and b5 reductases are not affected by both mutations . The cbl E mutation affects only the activity of methionine synthase . These results support the hypothesis that the early enzymatic steps of intracellular metabolism of cobalamin are similar in the synthesis of both methylcobalamin and adenosylcobalamin and these steps are altered by the cbl C and cbl D mutations . The tolerability and pharmacokinetics of the novel antimigraine compound DB00315 in healthy male volunteers . 1. DB00315 is a novel and selective agonist at P28221 receptors , with central and peripheral actions , currently in development for the acute oral treatment of migraine . 2 . The pharmacokinetic and tolerability profiles of single oral doses from 1-50 mg DB00315 were investigated in 12 healthy male volunteers in a double-blind , placebo-controlled , dose-escalating study . 3 . DB00315 was well tolerated with most adverse experiences of mild and transient nature . 4 . Absorption was rapid with dose-independent kinetics . Median tmax was 2-4 h although 50-85 % of eventual Cmax was attained within 1 h . The t1/2 was 2.5-3 h with a high apparent plasma clearance ( CL/F > 2000 ml min-1 ) and apparent volume of distribution ( Vz/F ) of 400-500 l . 5 . Three metabolites were detected in plasma and urine , one of which , the N-desmethyl metabolite , has P28221 agonist activity . 6 . DB00315 showed no clinically significant effects on blood pressure , heart rate , ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment . Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5- Q13049 receptors . Signaling pathways responsible for serotonin ( 5-HT ) -mediated induction of early response genes prostaglandin G/H synthase-2 ( P35354 , cyclooxygenase-2 ) and egr-1 were investigated in rat mesangial cells . Gene induction by 5-HT was dependent on 5- Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family . Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C ( P98160 ) and release of Ca2+ from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5-HT signaling . Instead , inhibition of phosphatidylcholine-specific P98160 interfered with P35354 and egr-1 mRNA induction , suggesting this enzyme as a link between 5- Q13049 receptors and protein kinase C , an essential part of 5-HT-mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr-1 mRNA expression by itself , but strongly inhibited 5-HT-mediated mRNA induction . P35354 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA , suggesting involvement of Ca2+-dependent enzymes . In contrast , egr-1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps . Activation of the Gq-coupled 5- Q13049 receptor thus leads to the expression of the early response genes P35354 and egr-1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively . Thrombosis is reduced by inhibition of P23219 , but unaffected by inhibition of P35354 , in an acute model of platelet activation in the mouse . BACKGROUND : Clinical use of selective inhibitors of cyclooxygenase ( P36551 ) -2 appears associated with increased risk of thrombotic events . This is often hypothesised to reflect reduction in anti-thrombotic prostanoids , notably P06744 (2) , formed by P35354 present within endothelial cells . However , whether P35354 is actually expressed to any significant extent within endothelial cells is controversial . Here we have tested the effects of acute inhibition of P36551 on platelet reactivity using a functional in vivo approach in mice . METHODOLOGY/PRINCIPAL FINDINGS : A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin ( 7 days orally as control ) diclofenac ( 1 mg.kg(-1) , i.v. ) and parecoxib ( 0.5 mg.kg(-1) , i.v. ) on thrombus formation induced by collagen or the thromboxane ( TX ) A(2)-mimetic , U46619 . The P36551 inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo . Collagen and U46619 caused in vivo thrombus formation with the former , but not latter , sensitive to oral dosing with aspirin . Diclofenac inhibited P23219 and P35354 ex vivo and reduced thrombus formation in response to collagen , but not U46619 . DB08439 inhibited only P35354 and had no effect upon thrombus formation caused by either agonist . CONCLUSIONS/SIGNIFICANCE : Inhibition of P23219 by diclofenac or aspirin reduced thrombus formation induced by collagen , which is partly dependent upon platelet-derived TXA(2) , but not that induced by U46619 , which is independent of platelet TXA(2) . These results are consistent with the model demonstrating the effects of P23219 inhibition in platelets , but provide no support for the hypothesis that acute inhibition of P35354 in the circulation increases thrombosis . DB09078 : first global approval . DB09078 ( Lenvima™ ) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1 , 2 and 3 , fibroblast growth factor receptors 1 , 2 , 3 and 4 , platelet-derived growth factor receptor α , P07949 and P10721 . In addition to their role in normal cellular function , these kinases have been implicated in pathogenic angiogenesis , tumour growth and cancer progression . DB09078 is being developed by Eisai Co . Ltd for the treatment of solid tumours , primarily for differentiated thyroid cancer , and other malignancies . A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic , progressive , radioactive iodine-refractory differentiated thyroid cancer . DB09078 is in pre-registration for this indication in the EU , Australia , Brazil , Canada , Japan , South Korea , Russia , Singapore and Switzerland , and is in phase 3 development in Argentina , Chile and Thailand . DB09078 has orphan designation in the EU and Japan for use in differentiated thyroid cancer . In addition , an ongoing global , phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma . This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic , progressive , radioactive iodine-refractory differentiated thyroid cancer . Characterization of 5- Q13049 receptor desensitization and the effect of cycloheximide on it in P13671 cells . Effect of prolonged pretreatment with serotonin ( 5-HT ) on 5- Q13049 receptor desensitization was examined by the measurement of intracellular calcium ( [Ca2+]i ) mobilization in P13671 cells . 5-HT-induced desensitization of [Ca2+]i mobilization was in a time and dose dependent manner and reached a plateau after 3 hr . After 1 and 3 hr 5-HT pretreatment , 5-HT concentration in the medium little changed . 5-HT pretreatment with cycloheximide , a protein synthesis inhibitor , produced an enhancement of the desensitization for 3 and 6 hr pretreatment . However , 5-HT pretreatment for 3 and 6 hr caused no marked change in the 5- Q13049 receptor mRNA level or Galphaq/11 protein in this study , suggesting that 5-HT may decrease 5-HT-induced [Ca2+]i mobilization independent of 5- Q13049 receptor mRNA or G-proteins . P05305 -induced [Ca2+]i mobilization did not alter after 5-HT and/or cycloheximide pretreatment . These results showed that activation of the 5- Q13049 receptor induced homologous desensitization and pretreatment with 5-HT and/or cycloheximide did not change the efficacy of the second messenger pathway from Gq to a [Ca2+]i rise . DB01131 resistance in Plasmodium falciparum African isolates : assessment by mutation-specific polymerase chain reaction and in vitro susceptibility testing . The antifolate proguanil is commonly used in the prophylaxis and treatment of Plasmodium falciparum malaria . A series of point mutations in the dihydrofolate reductase ( P00374 ) gene has been linked to differential susceptibility of varied P. falciparum clones or isolates to this drug . To survey the efficiency of proguanil prophylaxis in an African endemic region , and to evaluate the level of proguanil resistance in the corresponding parasite population , we performed drug susceptibility assays with P. falciparum isolates from Senegal , Kenya , and Niger . In parallel , we developed a mutation-specific polymerase chain reaction assay that enabled us to characterize mutations in the P00374 gene of the same isolates without in vitro parasite cultivation . We confirm previously available data showing that parasites harboring a point mutation from Ser108 to DB00174 present a decrease in susceptibility to cycloguanil ( the active metabolite of proguanil ) , and we show that mutations in codons 51 and 59 appear to modulate the level of resistance to cycloguanil . No mutations in codons 16 and 164 were detected in resistant parasites , in contrast with results from some previous studies . The genomic clone P08908 which resembles a beta-adrenergic receptor sequence encodes the P08908 receptor . The recent cloning of the complementary DNAs and/or genes for several receptors linked to guanine nucleotide regulatory proteins including the adrenergic receptors ( alpha 1 , alpha 2A , alpha 2B , beta 1 , beta 2 ) , several subtypes of the muscarinic cholinergic receptors , and the visual ' receptor ' rhodopsin has revealed considerable similarity in the primary structure of these proteins . In addition , all of these proteins contain seven putative transmembrane alpha-helices . We have previously described a genomic clone , P08908 , isolated by cross-hybridization at reduced stringency with a full length beta 2-adrenergic receptor probe . This clone contains an intronless gene which , because of its striking sequence resemblance to the adrenergic receptors , is presumed to encode a G-protein-coupled receptor . Previous attempts to identify this putative receptor by expression studies have failed . We now report that the protein product of the genomic clone , Q96NT5 , transiently expressed in monkey kidney cells has all the typical ligand-binding characteristics of the 5-hydroxytryptamine ( P08908 ) receptor . Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria . DB01131 and pyrimethamine are antifolate drugs with distinct chemical structures that are used commonly in the prophylaxis and treatment of Plasmodium falciparum malaria . Clinical reports and field studies have suggested that some parasites refractory to proguanil can be treated with pyrimethamine , and vice versa . Analysis of the P. falciparum dihydrofolate reductase ( P00374 ) from different parasites reveals the structural basis for differential susceptibility to these antifolate drugs . Parasites harboring a pair of point mutations from Ala-16 to DB00161 -16 and from DB00133 -108 to DB00156 -108 are resistant to cycloguanil ( the active metabolite of proguanil ) but not to pyrimethamine . A single DB00174 -108 mutation , on the other hand , confers resistance to pyrimethamine with only a moderate decrease in susceptibility to cycloguanil . Significant cross-resistance to both drugs occurs in parasites having mutations that include DB00133 -108 ---- DB00174 -108 and DB00167 -164 ---- DB00149 -164 . These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of P00374 . Alternative inhibitors , used alone or in combination , may be effective against some strains of cycloguanil- or pyrimethamine-resistant malaria . The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity-mortality of the illness . DB08815 is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5- Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . DB08815 was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents . Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin(1A) ( 5-HT(1A) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen-activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1.0 mg/kg ( s.c. ) , while the minimal dose for corticosterone release was 3.0 mg/kg ( s.c. ) . The ED(50) of tandospirone was 1.3 mg/kg for oxytocin , 1.2 mg/kg for DB01285 , 3.0 mg/kg for corticosterone , and 0.24 mg/kg for prolactin . Pretreatment with the specific 5-HT(1A) receptor antagonist WAY 100,635 ( 0.3 mg/kg , s.c. ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose-response curve for prolactin to the right . Tandospirone injection ( 10 mg/kg , s.c. ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 /44 extracellular signal-regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p- P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100,635 ( 0.3 mg/kg ) . The results are the first evidence that systemic 5-HT(1A) receptor agonist administration produces a rapid increase in p- P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5-HT(1A) receptor . Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8-hydroxy-DPAT ( 8-OH-DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3-10 , 10-17 or 17-24 ) were injected daily with 1 mg/kg 8-OH-DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye-opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10-17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17-24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin 's influence in brain development . P15121 regulates TGF-beta1-induced production of fibronectin and type IV collagen in cultured rat mesangial cells . AIM : To study the effects of aldose reductase ( AR ) on production of fibronectin and type IV collagen in rat mesangial cells ( MsC ) . METHODS : The vector , pcDNA3-AR , was constructed based on pET-15b-AR . Lipofect AMINE was used for stable transfection and G418 was used for selecting positive clones . DB02712 and zopolrestat were added for suppressing the activity of AR , respectively . The production of fibronectin and type IV collagen and the activation of Smads and MAPK signal transduction pathway were analysed by western blot and AP-1 activity was analysed by electrophoretic mobility shift assays ( EMSA ) . RESULTS : The normal MsC showed increased expression of fibronectin and type IV collagen with stimulation of TGF-beta1 . Compared with the normal MsC , the MsC pre-incubated with Q9Y4X5 showed reduced expression ( P < 0.05 ) and the AR-transfected MsC showed increased expression ( P < 0.05 ) . The normal MsC showed activation of P29323 , JNK and p38 with stimulation of TGF-beta1 , while the activation of JNK and p38 was inhibited in the MsC pre-incubated with Q9Y4X5 and only the activation of JNK was enhanced in the AR-transfected MsC . The normal MsC showed enhanced AP-1 activity with the stimulation of TGF-beta1 , and similarly the activity was inhibited in the MsC pre-incubated with Q9Y4X5 and was more enhanced in the AR transfected MsC . CONCLUSION : AR can regulate the expression of fibronectin and type IV collagen with the stimulation of TGF-beta1 in MsC , which may have relations with the activation of JNK-MAPK and p38-MAPK signalling pathways and AP-1 . delta- DB00855 dehydrase : a new genetic polymorphism in man . A method has been developed for the electrophoretic and quantitative analyses of human red cell delta-aminolevulinate dehydrase ( P13716 ) . The enzyme is under the control of an autosomal gene , with two common codominant alleles . ALADH1 and ALADH2 , with frequencies of 0.89 and 0.11 , respectively , in the Italian population . Mean phenotypic enzyme activities are nearly identical : 52, . 49 and 55 mIU/g Hb for P13716 1 , P35326 and 2 phenotypes respectively . Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress . Chronic stress is known to affect brain areas involved in learning and emotional responses . These changes , thought to be related to the development of cognitive deficits are evident in major depressive disorder and other stress-related pathophysiologies . The serotonin-related transcription factors ( Q6P1N0 / Q6P1N0 ; five prime repressor element under dual repression/coiled-coil P06681 domain 1a , and O75398 /Deaf-1 ; nuclear-deformed epidermal autoregulatory factor ) are two important regulators of the P08908 receptor . Using Western blotting and quantitative real-time polymerase chain reaction ( qPCR ) we examined the expression of mRNA and proteins for Q6P1N0 , O75398 , and the P08908 receptor in the prefrontal cortex ( P27918 ) of male rats exposed to chronic restraint stress ( CRS ; 6 h/day for 21 days ) . After 21 days of CRS , significant reductions in both Q6P1N0 mRNA and protein were observed in the P27918 ( 36.8 % and 32 % , respectively ; P < 0.001 ) , while the levels of both O75398 protein and mRNA did not change significantly . Consistent with reduced Q6P1N0 protein , P08908 receptor mRNA levels were equally upregulated in the P27918 , while protein levels actually declined , suggesting post-transcriptional receptor downregulation . The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Q6P1N0 and the P08908 receptor in the P27918 of the male rat while having no effect on O75398 . These results point to the importance of understanding the mechanism for the differential regulation of Q6P1N0 and O75398 in the P27918 as a basis for understanding the related effects of chronic stress on the serotonin system ( serotonin-related transcription factors ) and stress-related disorders like depression . DB00502 , but not clozapine , produces dramatic catalepsy in delta9-THC-treated rats : possible clinical implications . The effect on rat catalepsy induced by Delta9-tetrahydrocannabinol ( Delta9-THC ) in association with haloperidol ( HP ) or clozapine ( CLOZ ) administration was investigated . Delta9-THC dose-dependently increased HP ( 0.05-1 mg kg-1 , s.c. ) -induced rat catalepsy , while no catalepsy was observed after CLOZ ( 1-20 mg kg-1 , s.c. ) or Delta9-THC+CLOZ administration . The P21554 antagonist SR141716A ( 0.5-5 mg kg-1 , i.p. ) reversed the increase mediated by Delta9-THC on HP-induced catalepsy . The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP+Delta9-THC ; however , higher doses of quinpirole were needed in the presence of Delta9-THC . The M1 antagonist scopolamine and alpha2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP+Delta9-THC in a similar manner . CLOZ and the 5- Q13049 /2C antagonists ritanserin , RS102221 and SB242084 were more effective in antagonizing HP than HP+Delta9-THC-induced catalepsy.7 HP and CLOZ failed to inhibit in vitro [3H]CP-55,940 binding , while Delta9-THC and SR141716A did not show an appreciable affinity for the D2 receptor . It was suggested that the different effects on rat catalepsy induced by Delta9-THC following HP or CLOZ administration may depend on the receptor-binding profiles of the two antipsychotics . The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed . P15121 regulates high glucose-induced ectodomain shedding of tumor necrosis factor ( P01375 ) -alpha via protein kinase C-delta and P01375 converting enzyme in vascular smooth muscle cells . Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes , however , the mechanisms by which diabetes increases inflammation remain poorly understood . Here , we report that exposure to high glucose ( HG ) stimulates ectodomain shedding of P01375 from rat aortic smooth muscle cells in culture . Our results show that exposure to HG decreases membrane-associated P01375 . This decrease in unprocessed P01375 was prevented by the aldose reductase ( AR ) inhibitor sorbinil and AR small interference RNA . Treatment with HG , but not equimolar mannitol or 3-O-methyl glucose , resulted in phosphorylation and activation of P01375 converting enzyme ( P78536 ) ( P78536 ) , which were attenuated by sorbinil or AR-specific small interference RNA . HG-induced P78536 phosphorylation and P01375 processing were also prevented by P01375 protease inhibitor-1 , an inhibitor of P78536 . Inhibition of protein kinase C ( PKC ) -delta by rottlerin prevented HG-induced P78536 activation and the accumulation of unprocessed P01375 . Treatment with sorbinil decreased elevated levels of circulating P01375 in streptozotocin-treated diabetic rats . DB02712 treatment also decreased the expression of P01375 , matrix metalloproteinase-2 , matrix metalloproteinase-9 , and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats . These results indicate that HG-induced P01375 shedding could be attributed to P78536 activation , which is regulated , in part , by PKC-delta and AR . Therefore , inhibition of P78536 by P01375 protease inhibitor-1 , or pharmacological inhibition of PKC-delta or AR may represent useful strategies for treating vascular inflammation associated with diabetes . Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5-HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression/antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 -Flk-1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization . DB09078 is an oral multikinase inhibitor that selectively inhibits vascular endothelial growth factor ( P15692 ) receptors 1 to 3 and other proangiogenic and oncogenic pathway-related receptor tyrosine kinases . To elucidate the origin of the potency of lenvatinib in P15692 receptor 2 ( P35968 ) inhibition , we conducted a kinetic interaction analysis of lenvatinib with P35968 and X-ray analysis of the crystal structure of P35968 -lenvatinib complexes . Kinetic analysis revealed that lenvatinib had a rapid association rate constant and a relatively slow dissociation rate constant in complex with P35968 . Co-crystal structure analysis demonstrated that lenvatinib binds at its DB00171 mimetic quinoline moiety to the DB00171 binding site and to the neighboring region via a cyclopropane ring , adopting an DB00128 - DB00120 - DB00145 ( DFG ) - " in " conformation . These results suggest that lenvatinib is very distinct in its binding mode of interaction compared to the several approved P35968 kinase inhibitors . Potentiation by neuropeptide Y of 5HT2A receptor-mediated contraction in porcine coronary artery . Potentiation by neuropeptide Y of serotonin ( 5-HT ) -induced vasoconstriction was investigated in porcine coronary artery . 5-HT caused concentration-dependent contraction through 5- Q13049 receptors . Neuropeptide Y ( 30 nM ) significantly increased the 5HT-induced contraction by 16+/-5 % in arteries with intact endothelium . Removal of the endothelium abolished the potentiation . A neuropeptide Q03519 antagonist , BIBP3226 , blocked this neuropeptide Y-induced potentiation . In vessels with intact endothelium , the potentiation by neuropeptide Y was inhibited by in the presence of a cyclo-oxygenase inhibitor , indomethacin ( 30 microM ) , but not by the presence of P25101 or ETB endothelin receptor antagonists or an NO synthase inhibitor , NG-nitro-L-arginine ( DB04223 ) ( 1 mM ) at all . A thromboxane A2 ( TXA2 ) synthase inhibitor , ozagrel , and prostanoid TP receptor antagonists , seratrodast and ONO-3708 , also inhibited the neuropeptide Y-induced potentiation . In the endothelium-denuded arteries , a prostanoid TP receptor agonist , U-46619 ( 0.01-0.1 nM ) , potentiated 5-HT-induced contraction . These results indicate that neuropeptide Y potentiates the 5-HT-induced contraction , due to release of TXA2 from the endothelium via neuropeptide Q03519 receptors , in porcine coronary artery . Evidence that 5-HT2c receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety . Four non-selective P28335 /5- Q13049 receptor antagonists , mianserin ( 2-8 mg/kg ) , 1-naphthyl piperazine ( 1-NP ) ( 0.5-1 mg/kg ) , ICI 169,369 ( 20 mg/kg ) and LY 53857 ( 5 mg/kg ) , increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous ( SC ) administration . This property was shared by the benzodiazepine anxiolytic chlordiazepoxide ( 5 mg/kg SC ) . However , the selective 5- Q13049 receptor antagonists ketanserin ( 0. P35326 mg/kg SC ) and altanserin ( 0.5 , 1 mg/kg SC ) had little effect . The P08908 , P28222 and beta-adrenergic receptor antagonists pindolol and cyanopindolol ( 6 mg/kg SC ) did not affect punished responding either , nor did the P28221 receptor partial agonist and alpha 2 adrenergic receptor antagonist yohimbine ( 2.5 mg/kg SC ) or the histamine H1 receptor antagonist mepyramine ( 1 mg/kg SC ) . Unpunished responding was also modestly increased after some doses of the P28335 /5- Q13049 receptor antagonists . However , this effect was inconsistent and was also seen after chlordiazepoxide . Furthermore , it was not associated with the increase in punished responding observed in rats orally treated with mianserin ( 10 , 20 mg/kg ) , 1-NP ( 10 , 20 mg/kg ) or ICI 169,369 ( 50 mg/kg ) . The action of the P28335 /5- Q13049 receptor antagonists tested is therefore consistent with anxiolysis . The results also strongly suggest that this effect is mediated by blockade of the P28335 receptor , although the possibility of P41595 receptor mediation is discussed . DB00315 , a new central and peripherally acting P28221 receptor agonist in the acute oral treatment of migraine : a double-blind , placebo-controlled , dose-range finding study . DB00315 is a novel , centrally and peripherally , acting 5-hydroxytryptamine1D receptor agonist . We investigated the efficacy and safety of 1 , 5 , and 25 mg of oral DB00315 in the acute treatment of migraine in a randomized , double-blind , placebo-controlled , parallel-group clinical trial involving 84 patients . The proportion of patients in whom the headache improved within 2 hours from moderate or severe to mild or no pain ( primary efficacy measure ) was 15 % for placebo-treated patients and 27 % ( 1 mg ) , 62 % ( 5 mg ) , and 81 % ( 25 mg ) for patients treated with DB00315 . Treatment differences compared with placebo were 12 % ( 95 % CI - 12 , 37 ; p = 0.460 ) for 1 mg DB00315 , 47 % ( CI 21 , 73 ; p < 0.005 ) for 5 mg DB00315 , and 66 % ( CI 43,89 ; p < 0.001 ) for 25 mg DB00315 . Photophobia and nausea also showed improvement after DB00315 . Adverse events were generally mild and transient in all treatment groups . There were no clinically significant changes in ECG recordings , blood pressure , or laboratory tests . Oral DB00315 ( 5 and 25 mg ) is highly effective and well tolerated in the acute treatment of migraine . The response rates and treatment differences compared with placebo in this study suggest possible superiority over existing antimigraine therapies . This needs to be confirmed in formal comparative trials . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .