interacts_with DB00501?
DB00501 enhances antigen-specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti-ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB/c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1) , IgG(2a) and/or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE , IgG(1) and IgG(2a) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies . Differential sensitivity to cardiotonic drugs of cyclic AMP phosphodiesterases isolated from canine ventricular and sinoatrial-enriched tissues . A cardiac phosphodiesterase ( PDE ) which specifically hydrolyzes DB02527 and is inhibited by cyclic GMP has been suggested to be the site of action of new cardiotonic drugs . To investigate the effect of inhibitors , canine cyclic nucleotide PDEs were isolated from left ventricle and from sinoatrial node-enriched tissue , using identical techniques . Four PDE forms could be chromatographically resolved from each tissue , including a peak I PDE ( calmodulin-activated phosphodiesterase , P62158 -PDE ) , a peak II PDE ( cyclic GMP-stimulated phosphodiesterase , O00408 ) and a peak III PDE ( specific for cyclic AMP ) . The latter was further fractionated into two forms : One was inhibited by cyclic GMP and by the platelet antiaggregant AAL 05 ( CGI-PDE ) , and the second was insensitive to cyclic GMP and was inhibited by rolipram ( ROI-PDE ) . Reference PDE inhibitors , isobutyl-1-methylxanthine ( DB07954 ) and papaverine , nonselectively inhibited the four forms isolated from the two tissues . Cardiotonic drugs ( CI 930 , LY 181512 , piroximone , enoximone , and SK & F 94120 ) selectively inhibited CGI-PDE from ventricular tissue but were poorly active on both CGI-PDE and ROI-PDE from the sinoatrial-enriched fraction . In contrast , milrinone inhibited CGI-PDEs and ROI-PDEs from both ventricular and sinoatrial tissues . These results are in good agreement with pharmacologic data in the literature on the positive chronotropic and inotropic effects of the studied drugs in the dog . They provide a possible basis for the dissociation of these two properties of PDE inhibitors . Pressure overload induces Q14116 and IL-18R expression , but markedly suppresses O95998 expression in a rabbit model . Q14116 potentiates P01375 -α-induced cardiomyocyte death . Recurrent or sustained inflammation plays a causal role in the development and progression of left ventricular hypertrophy ( LVH ) and its transition to failure . Interleukin ( IL ) -18 is a potent pro-hypertrophic inflammatory cytokine . We report that induction of pressure overload in the rabbit , by constriction of the descending thoracic aorta induces compensatory hypertrophy at 4weeks ( mass/volume ratio : 1.7±0.11 ) and ventricular dilatation indicative of heart failure at 6weeks ( mass/volume ratio : 0.7±0.04 ) . In concordance with this , fractional shortening was preserved at 4weeks , but markedly attenuated at 6weeks . We cloned rabbit Q14116 , IL-18Rα , IL-18Rβ , and Q14116 binding protein ( O95998 ) cDNA , and show that pressure overload , while enhancing Q14116 and IL-18R expression in hypertrophied and failing hearts , markedly attenuated the level of expression of the endogenous Q14116 antagonist O95998 . Cyclical mechanical stretch ( 10 % cyclic equibiaxial stretch , 1Hz ) induced hypertrophy of primary rabbit cardiomyocytes in vitro and enhanced P01160 , Q14116 , and IL-18Rα expression . Further , treatment with rhIL-18 induced its own expression and that of IL-18Rα via AP-1 activation , and induced cardiomyocyte hypertrophy in part via PI3K/Akt/ P43694 signaling . In contrast , Q14116 potentiated P01375 -α-induced cardiomyocyte death , and by itself induced cardiac endothelial cell death . These results demonstrate that pressure overload is associated with enhanced Q14116 and its receptor expression in hypertrophied and failingrabbit hearts . Since O95998 expression is markedly inhibited , our results indicate a positive amplification in Q14116 proinflammatory signaling during pressure overload , and suggest Q14116 as a potential therapeutic target in pathological hypertrophy and cardiac failure . Active immunisation against pregnenolone reduces testicular steroidogenesis and DB00644 synthesis in rabbits . To investigate the effects of active immunisation against pregnenolone on reproductive traits in rabbits , 16 early pubertal male rabbits ( 4mo old ) were randomly and equally allocated into two groups , control or immunised against pregnenolone-hemisuccinate-BSA in Freund 's adjuvant ( with a booster 4wk later ) . Blood samples ( for antibody titres and hormone concentrations ) were collected at 2 or 4wk-intervals after immunisation until rabbits were killed , 24wk after the primary immunisation . Compared to controls , rabbits immunised against pregnenolone had increased serum antibody titres ( P < 0.01 ) and decreased serum concentrations of both testosterone and LH ( P < 0.01 for each ) . At 24wk after the primary immunisation , testes were severely atrophied , spermatogenesis was arrested and steroidogenesis was suppressed , as evidenced by lesser amounts of testicular cholesterol side-chain cleavage cytochrome P-450 and 17α-hydroxylase cytochrome P-450 mRNA ( P < 0.05 ) . Furthermore , the amounts of mRNA for DB00644 in the arcuate nucleus ( Arc ) , of the hypothalamus and P30968 and LH-β in the pituitary and genes in sex-hormone negative feedback loops ( androgen receptor , oestrogen alpha receptor , kisspeptin encoded gene and kisspeptin receptor ) in the Arc were decreased in pregnenolone-immunised rabbits compared to controls ( P < 0.05 ) . It was concluded that immunisation against pregnenolone directly blocked testicular steroidogenesis , which reduced synthesis of hypothalamic DB00644 and subsequently synthesis of pituitary LH by abolishing the permissive action of sex steroids on hypothalamic DB00644 neurons , thereby disrupting spermatogenesis . This was apparently the first report that active immunisation against pregnenolone was a means of immunological castration . DB11320 reduces susceptibility to natural killer cells via down-regulation of P26718 ligands on human monocytic leukaemia THP-1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry . Interferon-γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2-pyridylethylamine and P25021 agonist dimaprit down-regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine-induced down-regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription-PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down-regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down-regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity . These results suggest that histamine down-regulates P26718 ligands through the activation of an P35367 - and P25021 -mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells . Regulation of angiopoietin-like protein 4/fasting-induced adipose factor ( Angptl4/FIAF ) expression in mouse white adipose tissue and 3T3- Q9NUQ9 adipocytes . Q9BY76 ( Angptl4 ) /FIAF ( fasting-induced adipose factor ) was first identified as a target for Q07869 and to be strongly induced in white adipose tissue ( WAT ) by fasting . Here we have examined the regulation of the expression and release of this adipokine in mouse WAT and in 3T3- Q9NUQ9 adipocytes . Angptl4/FIAF expression was measured by RT-PCR and real-time PCR ; plasma Angptl4/FIAF and release of the protein in cell culture was determined by western blotting . The Angptl4/FIAF gene was expressed in each of the major WAT depots of mice , the mRNA level in WAT being similar to the liver and much higher ( > 50-fold ) than skeletal muscle . Fasting mice ( 18 h ) resulted in a substantial increase in Angptl4/FIAF mRNA in liver and muscle ( 9.5- and 21-fold , respectively ) ; however , there was no effect of fasting on Angptl4/FIAF mRNA in WAT and the plasma level of Angptl4/FIAF was unchanged . The Angptl4/FIAF gene was expressed in 3T3- Q9NUQ9 adipocytes before and after differentiation , the level increasing post-differentiation ; Angptl4/FIAF was released into the culture medium . P01308 , leptin , dexamethasone , noradrenaline , TNFalpha and several IL ( IL-1beta , P05231 , P22301 , Q14116 ) had little effect on Angptl4/FIAF mRNA levels in 3T3- Q9NUQ9 adipocytes . However , a major stimulation of Angptl4/FIAF expression was observed with rosiglitazone and the inflammatory prostaglandins PGD2 and PGJ2 . Angptl4/FIAF does not act as an adipose tissue signal of nutritional status , but is markedly induced by fasting in liver and skeletal muscle . P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell-surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration-response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed . Decreased expression of histamine H1 and H4 receptors suggests disturbance of local regulation in human colorectal tumours by histamine . Production of histamine in colon tumours has been described earlier . DB11320 -mediated signals have been shown to be implicated in tumour growth , and the effects of histamine are largely determined locally by the histamine receptor expression pattern . We analysed histamine receptor expression in human colorectal cancer , adenoma and normal mucosa by quantitative reverse transcription-polymerase chain reaction ( RT-PCR ) , Western blot analysis and immunostaining . Real-time RT-PCR results revealed significantly decreased ( p < 0.001 ) P35367 and Q9H3N8 mRNA levels in tumours compared to normal colonic mucosa , without any significant change in P25021 mRNA expression . Q9Y5N1 was absent in most samples ; it was detected at low levels in 7.9 % of the cases . Protein analysis showed a similar decrease in histamine receptor expression in carcinoma and adenoma compared to normal mucosa controls . Based on these results , we performed further Western blot analysis on Dukes-classified and -selected tumour samples . We found significantly decreased Q9H3N8 levels in neoplastic samples compared to normal colonic tissue , but there was no significant correlation between histamine receptor expression profile and the Dukes stage of tumours . Immunohistochemical staining revealed expression patterns of P35367 , P25021 and Q9H3N8 similar to those suggested by the mRNA and Western blot results . In the present study , we demonstrate that P35367 , P25021 and Q9H3N8 are expressed in colon carcinoma and the adjacent normal mucosa . The results suggest a dramatic alteration in the distribution of histamine receptors in colon cancer . These findings raise the perspective of targeted pharmacological studies with selective histamine receptor antagonists or agonists in the therapy of colorectal tumours . Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment . Myelodysplastic syndromes ( P43034 ) are common causes of ineffective hematopoiesis and cytopenias in the elderly . Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in P43034 . We have previously shown that p38 MAPK is overactivated in P43034 hematopoietic progenitors , which led to current clinical studies of the selective p38alpha inhibitor , DB05412 , in this disease . We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow ( BM ) cells in a p38 MAPK-dependent manner . Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with P28906 + stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment . Treatment with DB05412 inhibits P01375 secretion in primary P43034 bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo . Furthermore , p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells . These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival . These findings support clinical investigation of p38alpha as a potential therapeutic target in P43034 and other related diseases characterised by inflammatory bone marrow failure . Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production . AIMS : Peroxisome proliferator-activated receptor ( Q07869 ) -α is a transcription factor controlling lipid metabolism in liver , heart , muscle , and macrophages . Peroxisome proliferator-activated receptor-α activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver . However , the intestine expresses Q07869 -α , produces HDL and chylomicrons , and is exposed to diet-derived Q07869 -α ligands . Therefore , we examined the effects of Q07869 -α activation on intestinal lipid and lipoprotein metabolism . METHODS AND RESULTS : The impact of Q07869 -α activation was evaluated in term of HDL-related gene expression in mice , ex vivo in human jejunal biopsies and in Caco-2/TC7 cells . Apolipoprotein-AI/HDL secretion , cholesterol esterification , and trafficking were also studied in vitro . In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty acid oxidation genes , treatment with the dual Q07869 -α/δ ligand DB05187 resulted in a more pronounced increase in plasma HDL compared with fenofibrate in mice . DB05187 , but not fenofibrate , increased the expression of HDL production genes such as apolipoprotein-AI and DB00171 -binding cassette A1 transporter in murine intestines . A similar increase was observed upon Q07869 -α activation of human biopsies and Caco-2/TC7 cells . Additionally , HDL secretion by Caco-2/TC7 cells increased . Moreover , Q07869 -α activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells , modified cholesterol trafficking , and reduced apolipoprotein-B secretion . CONCLUSION : Peroxisome proliferator-activated receptor-α activation reduces cholesterol esterification , suppresses chylomicron , and increases HDL secretion by enterocytes . These results identify the intestine as a target organ of Q07869 -α ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia . DB00501 induces interleukin-18 production through H2-agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) -18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 production . DB00501 induced the activation of caspase-1 , which is reported to modify immature Q14116 to mature/active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers . Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice ( Hdc-/- mice ) with allergic airway inflammation . METHODS : Wild-type and Hdc-/- C57BL/6 mice were sensitized with ovalbumin ( OVA ) . After a 2-week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob-5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild-type mice and Hdc-/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc-/- mice with OVA inhalation compared to the wild-type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon-gamma ( P01579 ) , tumor necrosis factor-alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc-/- mice exposed to OVA was significantly higher than that in the wild-type mice under the same conditions . The mRNA levels of Gob-5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc-/- mice exposed to OVA compared to wild-type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation . Investigation of cholecystokinin system genes in panic disorder . There is evidence for the role of the cholecystokinin ( CCK ) neurotransmitter system in the neurobiology of panic disorder ( PD ) . The CCK receptor agonist , CCK-tetrapeptide ( Q13308 ) fulfills criteria for a panicogenic agent and there is evidence that PD might be associated with an abnormal function of the CCK system . For example , PD patients show an enhanced sensitivity to Q13308 , and exhibit lower P04141 and lymphocyte CCK concentration as compared to healthy controls ( reviewed by Bradwejn et al. ) . Also , untreated PD patients display an increased Q13308 -induced intracellular Ca2+ mobilization in T cells relative to treated PD , depression and schizophrenia . The CCK receptors have been classified into two subtypes : CCK-A and CCK-B . We report here a study of polymorphisms in the CCK pre-pro hormone gene ( CCK ) , P32238 , and P32239 in DSM-IV panic patients ( n = 99 ) vs controls matched for gender and ethnicity . The CCK polymorphism revealed no association with PD . We identified a new polymorphism for the P32238 gene , and tested it in our sample , with negative results . A single nucleotide polymorphism has been found in the coding region of the P32239 gene ( P32239 ) and D Collier ( personal communication ) identified a highly polymorphic dinucleotide (CT)n microsatellite in the 5' regulatory region . For the P32239 gene polymorphism , PD patients showed a significant association . Our genetic dissection of the CCK system thus far suggests that the P32239 gene variation may contribute to the neurobiology of panic disorder . Rational design of an P01133 - Q14116 fusion protein : implication for developing tumor therapeutics . Q14116 ( Q14116 ) is a proinflammatory cytokine . This protein has a role in regulating immune responses and exhibits significant anti-tumor activities . Epidermal growth factor ( P01133 ) is an important growth factor that plays a central role in the regulation of cell cycle and differentiation . It was proposed that a targeted delivery of Q14116 by generation of Q14116 - P01133 fusion protein might decrease adverse effects and result in enhancing cytotoxic and antitumor activities . In the present study , a fusion protein , consisting of P00533 binding domain fused to human Q14116 mature peptide via a linker peptide of ( DB00145 (4) DB00133 ) 3 , was constructed and expressed in the insect cell line Sf9 using Bac-to-Bac baculovirus expression system . We showed that the purified recombinant fusion protein induced similar levels of P01579 to that of native Q14116 protein in human PBMC in the presence of ConA . Furthermore , P01133 receptor competitive test in human epithelial cancer A431 cell line showed that P01133 - Q14116 fusion protein can specifically bind with P00533 by competing with native P01133 protein . These suggest that this rationally designed protein can be further developed as novel tumor therapeutics . High-throughput screening for kinase inhibitors . Following G protein-coupled receptors ( GPCRs ) , protein kinases have become the second most important class of targets for drug discovery over the last 20 years . While only four kinase inhibitors have reached the market to date ( Fasudil for rho-dependent kinase , DB00877 for TOR , Gleevec for P11274 -Abl , and DB00317 for P00533 ) , many more are already in clinical development . A historical overview of kinase inhibitors was recently published by Cohen . [ 1 ] After the previous successes , protein kinases are now regarded as attractive , well-drugable targets , and the analysis of the human genome has yielded 518 protein kinases . [ 2 ] We can thus expect screening for protein kinase inhibitors to become even more important in the future . In this review we will focus on the early steps of drug discovery programs producing new lead compounds . We will guide the reader through efficient state-of-the-art assay development and high-throughput screening of large chemical libraries for protein kinase inhibitors . DB00183 infusions in patients with panic disorder . I . Symptoms and cardiovascular responses . Cholecystokinin ( CCK ) may mediate human anxiety and animal data suggest that cholecystokinin antagonists could provide an important advance in the treatment of anxiety disorders . The study of CCK receptor systems in psychiatric patients has , however , been severely limited by the lack of available probes . We utilized intravenous infusions of pentagastrin , a selective P32239 agonist , and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls . DB00183 produced substantial symptomatology , including anxiety , and increases in heart rate and blood pressure , in both patients and controls . Patients were more sensitive to the panicogenic effects of the pentagastrin . Panic attacks occurred in 70 % of patients and 0 % of controls . Patients ' symptom responses were very similar to their " typical " panic attacks and to symptoms produced by Q13308 . DB00183 provides a readily available alternative to Q13308 for studying the CCK receptor system and exploring its involvement in human anxiety . Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by DB01221 receptors . The excitability of spinal neurons that transmit pain is modulated by glutamate and DB05875 ( SP ) . Glutamate is an excitatory neurotransmitter in the dorsal horn , and its effects are enhanced by SP acting on neurokinin 1 receptors ( NK1Rs ) . We assessed activation of NK1Rs by studying their internalization in spinal cord slices . NK1Rs were localized in sections from the slices by using immunohistochemistry combined with fluorescence and confocal microscopy . Incubating the slices with SP induced internalization in most P25103 -positive neurons in laminae I , IIo , and X and in half of P25103 -positive neurons in laminae III-V . SP-induced internalization was abolished by the specific P25103 antagonist L-703,606 ( 1 microM ) . Stimulating the dorsal root with long-duration ( 0.4 msec ) pulses evoked EPSPs in dorsal horn neurons with latencies consistent with the conduction speed of A partial differential- and C-fibers . High-frequency ( 100 Hz ) stimulation of the dorsal root with these pulses induced P25103 internalization in neurons in laminae I-IIo of the stimulated side of the slice but not in the contralateral side or in other laminae . Stimulation at lower frequencies ( 1 and 10 Hz ) failed to elicit significant internalization , suggesting that the release of SP is frequency-dependent . Internalization produced by the 100 Hz tetanus was mimicked by DB01221 and blocked by an DB01221 antagonist , 2-amino-5-phosphonopentanoic acid , but not by the AMPA and kainate antagonist CNQX . The P25103 antagonist L-703,606 abolished the internalization produced by 100 Hz stimulation or DB01221 . Therefore , the release of SP in the dorsal horn appears to be controlled by DB01221 receptors . Constitutively active Gq/11-coupled receptors enable signaling by co-expressed G(i/o)-coupled receptors . Co-expression of guanine nucleotide-binding regulatory ( G ) protein-coupled receptors ( GPCRs ) , such as the G(i/o)-coupled human P28222 ( 5-HT(1B)R ) , with the G(q/11)-coupled human histamine 1 receptor ( P35367 ) results in an overall increase in agonist-independent signaling , which can be augmented by 5-HT(1B)R agonists and inhibited by a selective inverse 5-HT(1B)R agonist . Interestingly , inverse P35367 agonists inhibit constitutively P35367 -mediated as well as 5-HT(1B)R agonist-induced signaling in cells co-expressing both receptors . This phenomenon is not solely characteristic of 5-HT(1B)R ; it is also evident with muscarinic M2 and adenosine A1 receptors and is mimicked by mastoparan-7 , an activator of G(i/o) proteins , or by over-expression of Gbetagamma subunits . Likewise , expression of the G(q/11)-coupled human cytomegalovirus ( HCMV ) -encoded chemokine receptor US28 unmasks a functional coupling of G(i/o)-coupled P32246 receptors that is mediated via the constitutive activity of receptor US28 . Consequently , constitutively active G(q/11)-coupled receptors , such as the P35367 and HCMV-encoded chemokine receptor US28 , constitute a regulatory switch for signal transduction by G(i/o)-coupled receptors , which may have profound implications in understanding the role of both constitutive GPCR activity and GPCR cross-talk in physiology as well as in the observed pathophysiology upon HCMV infection . Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer 's disease animal model . Harboring the behavioral and histopathological signatures of Alzheimer 's disease ( AD ) , senescence accelerated mouse-prone 8 ( SAMP8 ) mice are currently considered a robust model for studying AD . However , the underlying mechanisms , prioritized pathways and genes in SAMP8 mice linked to AD remain unclear . In this study , we provide a biological interpretation of the molecular underpinnings of SAMP8 mice . Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2 , 6 , and 12 months of age using cDNA microarray analysis . On the basis of PPI , MetaCore and the co-expression network , we constructed a distinct genetic sub-network in the brains of SAMP8 mice . Next , we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice . We found abnormal gene expression of P04049 , P10636 , P35354 , CDKN2A , Q9UQM7 , Q16620 , Q15109 , P25098 , O60318 , and Q9UNE7 , which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice . Specifically , we found microRNAs , including miR-20a , miR-17 , miR-34a , miR-155 , miR-18a , miR-22 , miR-26a , miR-101 , miR-106b , and miR-125b , that might regulate the expression of nodes in the sub-network . Taken together , these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective . P34947 regulates beta 1-adrenergic receptor association with P78352 . We previously reported that the beta(1)-adrenergic receptor ( beta(1)AR ) associates with P78352 through a PDZ domain-mediated interaction , by which P78352 modulates beta(1)AR function and facilitates the physical association of beta(1)AR with other synaptic proteins such as N-methyl-d-aspartate receptors . Here we demonstrate that beta(1)AR association with P78352 is regulated by P34947 ( P34947 ) . When beta(1)AR and P78352 were coexpressed with either P25098 or P34947 in COS-7 cells , P34947 alone dramatically decreased the association of beta(1)AR with P78352 , although P25098 and P34947 both could be co-immunoprecipitated with beta(1)AR and both could enhance receptor phosphorylation in vivo . Increasing expression of P34947 in the cells led to further decreased beta(1)AR association with P78352 . Stimulation with the beta(1)AR agonist isoproterenol further decreased P78352 binding to beta(1)AR . In addition , P34947 protein kinase activity was required for this regulatory effect since a kinase-inactive P34947 mutant had no effect on P78352 binding to beta(1)AR . Moreover , the regulatory effect of P34947 on beta(1)AR association with P78352 was observed only when P34947 was expressed together with the receptor , but not when P34947 was coexpressed with P78352 . Thus , we propose that P34947 regulates beta(1)AR association with P78352 through phosphorylation of beta(1)AR . Regulation of protein association through receptor phosphorylation may be a general mechanism used by G protein-coupled receptors that associate via PDZ domain-mediated protein/protein interactions . Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis . BACKGROUND : Interstitial cystitis/painful bladder syndrome ( IC/PBS ) is a bladder disease that causes debilitating pelvic pain of unknown origin , and IC/PBS symptoms correlate with elevated bladder lamina propria mast cell counts . Similar to IC/PBS patients , pseudorabies virus ( PRV ) infection in mice induces a neurogenic cystitis associated with bladder lamina propria mast cell accumulation and pelvic pain . We evaluated several drugs to determine the effectiveness of reducing PRV-induced pelvic pain . METHODS : Neurogenic cystitis was induced by the injection of Bartha 's strain of PRV into the abductor caudalis dorsalis tail base muscle of female C57BL/6 mice . Therapeutic modulation of pelvic pain was assessed daily for five days using von Frey filament stimulation to the pelvic region to quantify tactile allodynia . RESULTS : Significant reduction of PRV-induced pelvic pain was observed for animals treated with antagonists of neurokinin receptor 1 ( P25103 ) and histamine receptors . In contrast , the P35367 antagonist hydroxyzine , proton pump inhibitors , a histamine receptor 3 agonist , and gabapentin had little or no effect on PRV-induced pelvic pain . CONCLUSION : These data demonstrate that bladder-associated pelvic pain is attenuated by antagonists of P25103 and P25021 . Therefore , P25103 and P25021 represent direct therapeutic targets for pain in IC/PBS and potentially other chronic pain conditions . Selective peroxisome proliferator-activated receptor α modulators ( SPPARMα ) : the next generation of peroxisome proliferator-activated receptor α-agonists . Dyslipidemia is a major risk factor for cardiovascular ( CV ) disease - the primary cause of death , worldwide . Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk , a high level of residual risk persists , especially in people with obesity-related conditions , such as metabolic syndrome and type 2 diabetes mellitus . Q07869 - ( PPARα- ) agonists ( e.g. fibrates ) , play a central role in the reduction of macro- and microvascular risk in these patients . However , the currently available fibrates are weak ( PPARα-agonists ) with limited efficacy due to dose-related adverse effects . To address this problem , a new generation of highly potent and selective PPARα-modulators ( SPPARMα ) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects . Among these , aleglitazar ( a dual PPARα/γ agonist ) and DB05187 ( a dual Q07869 α/δ agonist ) have recently entered late-phase development . Although both compounds are more potent PPARα-activators than fenofibrate in vitro , only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol ( HDL-C ) in humans . However , it is also associated with a potential risk of adverse effects . More recently , a highly potent , specific PPARα-agonist ( K-877 ) has emerged with SPPARMα characteristics . Compared to fenofibrate , K-877 has more potent PPARα-activating efficacy in vitro , greater effects on triglycerides- and HDL-C levels in humans , and a reduced risk of adverse effects . If successful , K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes . Production of paired helical filament , tau-like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron-like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) -like antigen when they are subjected to heat shock ( Wallace et al. : Mol Brain Res 19:149-155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N- and C-terminal halves and the microtubule-binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full-length and C-terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF-like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer 's disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and/or degeneration of P10636 in Alzheimer 's disease . Activation of histamine H4 receptor inhibits TNFα/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells . Apoptosis is involved in the pathogenesis of Sjögren 's syndrome ( SS ) , an autoimmune disease affecting exocrine glands . Our recent studies revealed diminished histamine H4 receptor ( H₄R ) expression and impaired histamine transport in the salivary gland epithelial cells in SS . The aim was now to test if nanomolar histamine and high-affinity H₄R signaling affect apoptosis of human salivary gland epithelial cell . Simian virus 40-immortalized acinar NS-SV-AC cells were cultured in serum-free keratinocyte medium ± histamine H₄R agonist HST-10 . Expression and internalization of H₄R were studied by immunofluorescence staining ± clathrin inhibitor methyl-β-cyclodextrin ( MβCD ) . Apoptosis induced using tumor necrosis factor-α with nuclear factor-κB inhibitor IMD-0354 was studied using phase contrast microscopy , Western blot , flow cytometry and polymerase chain reaction ( qRT-PCR ) . HST-10-stimulated H₄R internalization was inhibited by MβCD . Western blotting revealed diminished phosphorylated c-Jun N-terminal kinase JNK , but unchanged levels of phosphorylated extracellular signal regulated kinase pERK1/2 in H₄R-stimulated samples compared to controls . qRT-PCR showed up-regulated expression of anti-apoptotic B cell lymphoma-extra large/Bcl-xL mRNAs and proteins , whereas pro-apoptotic Bcl-2-associated X protein/ Q07812 remained unchanged in Q9H3N8 -stimulated samples . H₄R stimulation diminished cleavage of PARP and flow cytometry showed significant dose-dependent inhibitory effect of H₄R stimulation on apoptosis . As far as we know this is the first study showing inhibitory effect of H₄R activation on apoptosis of human salivary gland cells . Diminished H₄R-mediated activation may contribute to loss of immune tolerance in autoimmune diseases and in SS in particular . p38 Q96HU1 kinase regulates stem cell apoptosis in human hematopoietic failure . Myelodysplastic syndromes ( P43034 ) are clonal stem cell disorders that lead to ineffective hematopoiesis and are common causes of low blood counts in the elderly . The exact molecular mechanisms regulating increased stem apoptosis in these disorders are not well defined . p38 MAPK activation is important in regulating the growth inhibitory signals of P01375 , TGF-beta and Interferons on human hematopoiesis . Our findings show that p38 MAPK is overactivated in myelodysplasia bone marrows and regulates hematopoietic stem cell apoptosis . Inhibition of p38 MAPK by genetic or pharmacologic means decreases apoptosis and stimulates in vitro hematopoiesis from primary P43034 hematopoietic progenitors . These studies point to the potential efficacy of selective p38alpha inhibitor , DB05412 , in human bone marrow failure . Disposition and metabolism of almotriptan in rats , dogs and monkeys . DB00918 is a new highly potent selective P28222 /1D receptor agonist developed for the treatment of migraine , and the disposition of almotriptan in different animal species is now addressed in the current study . DB00918 was well absorbed in rats ( 69.1 % ) and dogs ( 100 % ) following oral treatment . The absolute bioavailability was variable reflecting different degrees of absorption and first-pass metabolism ( 18.7-79.6 % ) . The elimination half-life was short and ranged between 0.7 and 3 h . The main route of elimination of almotriptan was urine with 75.6 % and 80.4 % of the dose recovered over a 168-h period in rats and dogs , respectively . The gamma-aminobutyric acid metabolite formed by oxidation of the pyrrolidine ring was the main metabolite found in urine , faeces , bile , and plasma of rats and in monkey urine . By contrast , the unchanged drug , the indole acetic acid metabolite formed by oxidative deamination of the dimethylaminoethyl group , and the N-oxide metabolite were the main metabolites in dog . DB00133 residues 338 and 339 in the carboxyl-terminal tail of the type II gonadotropin-releasing hormone receptor are critical for beta-arrestin-independent internalization . Cloned mammalian type II DB00644 receptors have a carboxyl-terminal tail in contrast to the mammalian type I DB00644 receptors , which uniquely lack a carboxyl-terminal tail . Because this domain mediates internalization of many serpentine receptors , the internalization pathway of the marmoset monkey type II P30968 and the functional role of the carboxyl-terminal tail in internalization was studied . The internalization pathway of the type II P30968 was investigated in COS-1 cells by coexpressing G protein-coupled receptor kinases ( GRKs ) , dynamin-1 , and beta-arrestins . Internalization of the receptor requires GRKs and dynamin but does not require beta-arrestin . The type II P30968 can also internalize via beta-arrestin in the presence of exogenous beta-arrestins , suggesting that the receptor can use two distinct internalization pathways . Receptor internalization appears to occur via clathrin-coated pits and caveolae because disruption of either structure inhibits internalization . Progressive truncations of the carboxyl-terminal tail identified a region containing serine residues 338 and 339 as critical for receptor internalization . Substitution of these serine residues with alanine residues inhibited internalization , whereas substitutions with glutamic acid residues rescued internalization . Furthermore , a dominant-negative P25098 did not inhibit internalization of receptors having these serine substitutions , although it inhibited internalization of the wild-type receptor . These results together identify serine residues 338 and 339 in the carboxyl-terminal tail as critical for internalization of the type II P30968 and suggest that these residues undergo phosphorylation by GRKs . However , neither of these residues , nor the carboxyl-terminal tail , is required for beta-arrestin-dependent internalization . Interferon-alpha promotes the anti-proliferative effect of gefitinib ( DB00317 ) on human colon cancer cell lines . OBJECTIVE : Interferon-alpha ( IFN alpha ) treatment is associated with up-regulation of epidermal growth factor receptor ( HER 1/ P00533 ) expression and marked growth inhibition of colon cancer cell lines in vitro . We aimed to determine the effect of combining IFN alpha and gefitinib on colon cancer cell line growth . METHODS : A panel of nine colon cancer cell lines were characterised for expression of HER 1/ P00533 and then treated with gefitinib alone , or IFN alpha alone , or IFN alpha plus gefitinib , following a pre-treatment using vehicle or IFN alpha . Crystal violet staining and flow cytometry were used to assess cell proliferation and expression of HER 1/ P00533 . The indexes and statistical assays were used to evaluate significant differences between treatment groups against vehicle control . RESULTS : All cell lines except SW 620 were HER 1/ P00533 positive . IFN alpha treatment was associated with significant up-regulation of cell surface HER 1/ P00533 expression in all HER 1/ P00533 -positive cell lines except KM 12 SM . Concurrent treatment with IFN alpha and gefitinib , or IFN alpha pre-treatment followed by gefitinib , or IFN alpha pre-treatment followed by a combination of IFN alpha plus gefitinib , additively or supra-additively/synergistically enhanced the sensitivity of the seven HER 1/ P00533 -up-regulated cell lines . CONCLUSION : IFN alpha improves the anti-proliferative effect of P00533 inhibition in colorectal cancer cell lines . This approach may have clinical implications for improving treatment based on targeting of HER 1/ P00533 . Human oviductal gonadotropin-releasing hormone : possible implications in fertilization , early embryonic development , and implantation . The oviduct is host to gametes and early embryos at a critical point in their lives . It is clear that the interactions of gametes/early embryo with the maternal oviduct in an autocrine and paracrine manner provide a microenvironment that enhances fertilization , early embryonic development , and implantation . Moreover , there is considerable evidence that an extrahypothalamic DB00644 may play a substantial role as a molecular autocrine/paracrine regulator in these events . Gametes and preimplantation embryos express DB00644 and P30968 at both messenger ribonucleic acid ( mRNA ) and protein levels . However , whether DB00644 is produced by the human oviduct has not yet been demonstrated . We used RT-PCR and immunohistochemical techniques to investigate DB00644 mRNA and protein expression in human fallopian tubes throughout the menstrual cycle of premenopausal fertile patients . Our results , at both the mRNA and protein levels , revealed cycle-dependent production of an oviductal DB00644 with expression during the luteal phase . Moreover , DB00644 immunostaining was localized in the tubal epithelium during the luteal phase . On the basis of these data , we suggest that during reproductive life , oviductal DB00644 may play a substantial paracrine/autocrine role in human fertilization , early embryonic development , and implantation . Molecular response of HL-60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis-related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl-2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis-arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis-related genes ( P10415 , Q07812 , Q9HB09 , CASPASE-3 , FAS ) after leukemia cell ( HL-60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT-PCR , using gene-specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis-related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis-related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug-specific and time-dependent manner . A novel O00408 reporter cell line : characterization of the cellular activity of PDE inhibitors . We report here the generation and pharmacological characterization of a phosphodiesterase 2A ( O00408 ) reporter cell line . Human O00408 was stably transfected in a parental cell line expressing the atrial natriuretic peptide ( P01160 ) receptor and the cyclic nucleotide-gated ( CNG ) cation channel Q16280 , acting as the biosensor for intracellular cGMP . In this reporter cell line , cGMP levels can be monitored in real-time via aequorin luminescence stimulated by calcium influx through the CNG channel . By using different PDE inhibitors , we could show that our O00408 reporter assay specifically monitors O00408 inhibition with high sensitivity . In the absence of P01160 stimulation , the O00408 selective inhibitors EHNA , BAY 60-7550 and Q9P0J1 did not increase basal luminescence levels in this experimental setting . However , in combination with P01160 , these inhibitors stimulated luminescence signals and induced leftward shifts of P01160 concentration-response curves . Similar results were obtained when using DB07954 , trequinsin and dipyridamole , which inhibit O00408 nonselectively with lower potency . Q9P0J1 , the most potent O00408 inhibitor known to date , was found to exhibit much lower cellular activity as anticipated from its biochemical O00408 inhibitory activity . By cellular uptake and transport studies we could show that Q9P0J1 's cell permeability is low and that the compound is a substrate for an efflux transporter . Other PDE inhibitors including vinpocetine , milrinone , rolipram , sildenafil , zaprinast , O95696 50481 and BAY 73-6691 did not stimulate luminescence signals on our O00408 reporter cell line . The results imply that this novel O00408 reporter assay provides an efficient , high throughput means for the identification and characterization of O00408 inhibitors . [ Roles of P26718 in cytokine-induced killer ( CIK ) against hematological malignant cells lines ] . This study was purposed to investigate the CIK cell cytotoxicity to hematological malignant cell lines by interaction P26718 receptors and corresponding ligands . The CIK cells was expanded from healthy individual with interferon (IFN)γ , CD3 monoclonal antibodies ( mAb ) and interleukin-2 ( P60568 ) . The subset of lymphocyte and the expression of NK cell receptors on CIK cells was detected by flow cytometry ; P26718 ligand expression on hematological malignant cell lines was also analyzed by flow cytometry , the calcein acetoxymethyl ester ( P62158 ) was used for labeling target cells , then the cytotoxicity of CIK cells to hematological malignant cell lines was detected by flow cytometry . The results showed that most of CIK cells expressed CD3 ( 97.85 ± 1.95 % ) , CD3(+)CD8(+) cells and CD3(+)CD56(+) cells increased significantly as compared with un-cultured cells ( P < 0.001;P = 0.033 ) . About 86 % CIK cells expressed P26718 receptor but no other NK receptors such as CD158a , CD158b and NCR . Different levels of P26718 ligands were detected in hematological malignant cell lines U266 , K562 and Daudi . CIK cells showed high cytotoxicity to these three different cell lines , and this cytotoxicity was partially blocked by treating CIK cells with anti- P26718 antibody ( U266 52.67 ± 4.63 % vs 32.67 ± 4.81 % , P = 0.008;K562 71.67 ± 4.91 % vs 50.33 ± 4.91 % , P = 0.007;Daudi 68.67 ± 5.04 vs 52.67 ± 2.60 % , P = 0.024 ) . It is concluded that most of CIK cells express P26718 receptor , interaction of P26718 - P26718 ligands may be one of the mechanisms , by which CIK cells kill hematological malignant cells . Granulocyte macrophage-colony stimulating factor increases the expression of histamine and histamine receptors in monocytes/macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage-colony-stimulating factor ( GM- P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine-producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM- P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM- P04141 -induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC-expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM- P04141 was also detected in the lesions . In U937 cells , GM- P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM- P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM- P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells . The presence of histamine-producing macrophages and gene expression of histamine receptors and GM- P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM- P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM- P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression . Cholecystokinin ( CCK ) stimulates aldosterone secretion from human adrenocortical cells via CCK2 receptors coupled to the adenylate cyclase/protein kinase A signaling cascade . Cholecystokinin ( CCK ) IS a regulatory peptide that acts via two receptor subtypes , P32238 and P32239 . RT-PCR demonstrated the expression of both P32238 and P32239 in the zona glomerulosa ( ZG ) , but not zona fasciculata-reticularis cells of the human adrenal cortex . CCK and the P32239 agonist pentagastrin enhanced basal aldosterone secretion from ZG cells without affecting cortisol production from zona fasciculata-reticularis cells . The aldosterone response to CCK and pentagastrin was suppressed by a P32239 antagonist , but not by a P32238 antagonist . DB00183 evoked a sizeable DB02527 , but not inositol triphosphate , response from ZG cells , whereas CCK plus P32239 antagonist was ineffective . The DB02527 response to pentagastrin was abrogated by P32239 antagonist or the adenylate cyclase inhibitor SQ-22536 , and the aldosterone response was abolished by both SQ-22536 and the protein kinase A inhibitor H-89 . Both CCK and pentagastrin increased steroidogenic acute regulatory protein mRNA expression in ZG cells ; the effect was abrogated by P32239 antagonist . We conclude that CCK exerts secretagogue action on human ZG cells , acting through CCK2-Rs coupled to the adenylate cyclase/protein kinase A signaling cascade , which , in turn , stimulates the expression of steroidogenic acute regulatory protein , the rate-limiting step of steroidogenesis . How does almotriptan compare with other triptans ? A review of data from placebo-controlled clinical trials . DB00918 , the new selective P28222 /1D agonist , has a higher oral bioavailability than any other DB00669 , with more than two thirds of the administered dose absorbed within the first hour both inside and outside of a migraine attack . Gender or the presence of food in the stomach does not affect its pharmacokinetic profile , and the compound has no clinically relevant interactions with other drugs . Among the available triptans , response rates at 2 hours range from 50 % to 80 % , with 20 % to 50 % of patients pain-free . DB00918 12.5 mg provides similar efficacy , with significant advantage over placebo at 30 minutes and a reliable consistency ( 75 % in two of three attacks ) . Headache typically recurs in 25 % to 45 % of patients with most triptans . The recurrence rate with almotriptan 12.5 mg , 18 % to 27 % , is among the lowest reported . The tolerability of almotriptan 12.5 mg is close to that of placebo with a low incidence of central nervous system side effects and chest symptoms . In conclusion , almotriptan 's consistent pharmacokinetics and good efficacy , in combination with excellent tolerability , make it an attractive choice in the acute treatment of migraine attacks . Coupling of serotonergic input to DB01221 receptor-phosphorylation following peripheral nerve injury via rapid , synaptic up-regulation of P03891 . Evidence implicates serotonergic input to spinal dorsal horn neurons in shifting the DB01221 receptor ( NMDAR ) into a high functional output profile after spinal nerve ligation ( Q16658 ) . We investigated the involvement of adaptor protein P03891 ( P03891 ) in NMDAR-phosphorylation and spinal hyperexcitability secondary to peripheral nerve injury . Immunofluorescence for P03891 was found in dorsal horn neurons immunopositive for NMDAR subunit Q9UHB4 . Co-localization of P03891 with postsynaptic marker P78352 was significantly increased 60min after Q16658 ( Rr 0.77 vs Rr 0.06 in sham controls ; z=-242.85 ; p < 0.01 at Fisher 's exact test ) . Western blot analyses confirmed P03891 up-regulation both in cytoplasmic ( S2 ) and synaptic ( P09131 ) compartments ( p < 0.01 at the Student 's t test ) . Q16658 was followed by increased co-localization of P03891 with the phosphorylated form ( serine 896 ) of Q9UHB4 ( pNMDA ) . Spinal superfusion with P03891 inhibitor rotenone prevented up-regulation of P03891 ( Rr 0.06 after rotenone vs Rr 0.78 in vehicle-treated controls , z=-253.22 , p < 0.01 ) and pNR1 in P09131 . C fiber-evoked dorsal horn field potentials were increased 60min after Q16658 by superfusion with DB01221 agonist cis-ACPD at 100nM ( p < 0.01 at the Bonferroni test ) , however cis-ACPD was effective only at 10μM following prior administration of rotenone . Rotenone also abolished enhancement of evoked potentials induced by simultaneous stimulation of DB01221 and 5-HR2B receptors in uninjured rats . Increased postsynaptic up-regulation of P03891 /pNMDAR 60min after Q16658 was prevented by prior administration of selective P41595 antagonist SB204741 . These results support a pivotal role for P03891 in coupling serotonergic input to NMDAR-activation during neuropathic pain .