interacts_with DB00486?
Q03135 interacts with 5- Q13049 serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors . 5-Hydroxytryptamine 2A ( 5-HT(2A) ) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction , platelet aggregation , and the modulation of perception , cognition , and emotion . In a search for 5-HT(2A) receptor-interacting proteins , we discovered that caveolin-1 ( Cav-1 ) , a scaffolding protein enriched in caveolae , complexes with 5-HT(2A) receptors in a number of cell types including P13671 glioma cells , transfected P29320 -293 cells , and rat brain synaptic membrane preparations . To address the functional significance of this interaction , we performed RNA interference-mediated knockdown of Cav-1 in P13671 glioma cells , a cell type that endogenously expresses both 5-HT(2A) receptors and Cav-1 . We discovered that the in vitro knockdown of Cav-1 in P13671 glioma cells nearly abolished 5-HT(2A) receptor-mediated signal transduction as measured by calcium flux assays . RNA interference-mediated knockdown of Cav-1 also greatly attenuated endogenous Galpha(q)-coupled P2Y purinergic receptor-mediated signaling without altering the signaling of P25116 thrombin receptors . Cav-1 appeared to modulate 5-HT(2A) signaling by facilitating the interaction of 5-HT(2A) receptors with Galpha(q) . These studies provide compelling evidence for a prominent role of Cav-1 in regulating the functional activity of not only 5-HT(2A) serotonin receptors but also selected Galpha(q)-coupled receptors . Thrombin receptors and their antagonists : an update on the patent literature . IMPORTANCE OF THE FIELD : Thrombin plays a central role in cardiovascular inflammation . Most of the cellular responses to thrombin are mediated by cell surface protease-activated receptors ( PARs ) . Several preclinical studies indicate that PARs are potential targets for treating cardiovascular diseases such as thrombosis , atherosclerosis and restenosis . Among PARs , P25116 has emerged as an important therapeutic target . AREAS COVERED IN THIS REVIEW : This review covers recent advances in the development of thrombin receptors antagonists . It is focused on the search for P25116 antagonists as this is at the moment the most promising and attractive target . However , some early promising studies on PAR-3 and -4 antagonists are also reported . WHAT THE READER WILL GAIN : The review has been written in order to give to the reader hints and references that cover , in our opinion , the most interesting and/or promising approaches in this research field . TAKE HOME MESSAGE : Research on P25116 antagonists has finally led to good clinical candidates such as DB05692 ( Schering-Plough ) and E-5555 ( Eisai Co. ) . Clinical trials clearly demonstrate that development of PAR1 antagonists is not only possible but most likely will lead to development of antiplatelet drugs as well as of drugs useful for the treatment of inflammatory , proliferative and neurodegenerative diseases . Activation of large-conductance , Ca2+-activated K+ channels by cannabinoids . We have examined the effects of the cannabinoid anandamide ( AEA ) and its stable analog , methanandamide ( methAEA ) , on large-conductance , Ca2+-activated K+ ( BK ) channels using human embryonic kidney ( P29320 ) -293 cells , in which the alpha-subunit of the Q12791 ( BK-alpha ) , both alpha- and beta1-subunits ( BK-alphabeta1 ) , or both alpha- and beta4-subunits ( BK-alphabeta4 ) were heterologously expressed . In a whole cell voltage-clamp configuration , each cannabinoid activated BK-alphabeta1 within a similar concentration range . Because methAEA could potentiate BK-alpha , BK-alphabeta1 , and BK-alphabeta4 with similar efficacy , the beta-subunits may not be involved at the site of action for cannabinoids . Under cell-attached patch-clamp conditions , application of methAEA to the bathing solution increased Q12791 activity ; however , methAEA did not alter channel activity in the excised inside-out patch mode even when DB00171 was present on the cytoplasmic side of the membrane . Application of methAEA to P29320 -BK-alpha and P29320 -BK-alphabeta1 did not change intracellular Ca2+ concentration . Moreover , methAEA-induced potentiation of Q12791 currents was not affected by pretreatment with a P21554 antagonist ( AM251 ) , modulators of G proteins ( cholera and pertussis toxins ) or by application of a selective CB2 agonist ( JWH133 ) . Inhibitors of P62158 , PKG , and MAPKs ( W7 , KT5823 , and PD-98059 ) did not affect the potentiation . Application of methAEA to mouse aortic myocytes significantly increased Q12791 currents . This study provides the first direct evidence that unknown factors in the cytoplasm mediate the ability of endogenous cannabinoids to activate Q12791 currents . Cannabinoids may be hyperpolarizing factors in cells , such as arterial myocytes , in which BK channels are highly expressed . Role of cyclooxygenase-2 in the prolonged regulation of renal function . The role of cyclooxygenase-2 ( P35354 ) in the prolonged regulation of renal function was evaluated during changes in sodium intake and reduction of NO synthesis . It was evaluated in conscious dogs by administering a selective inhibitor ( nimesulide ) during 8 consecutive days . DB04743 administration to dogs with normal or high sodium load did not modify glomerular filtration rate but reduced renal blood flow ( 16 % ; P < 0.05 ) . The vasoconstriction elicited by P35354 inhibition was greater when NO production was inhibited because glomerular filtration rate decreased by > 25 % when nimesulide was administered to dogs with a reduced NO synthesis . During low sodium intake , P35354 inhibition elicited a decrease ( P < 0.05 ) of both glomerular filtration rate ( 34 % ) and renal blood flow ( 31 % ) . Sodium excretion only decreased ( P < 0.05 ) during the first day of P35354 inhibition in dogs with normal or high sodium load . The increase in plasma potassium levels elicited by P35354 inhibition was greater in dogs with low sodium intake and was enhanced when NO production was inhibited . This change in potassium was not secondary to a decrease in plasma aldosterone levels . The results of this study suggest that P35354 -derived metabolites ( 1 ) play a more important role in the long-term regulation of renal hemodynamic when sodium intake is low , ( 2 ) protect the renal vasculature from the vasoconstriction secondary to a reduction in NO , ( 3 ) are only acutely involved in regulating urinary sodium excretion , and ( 4 ) play a more important role in regulating plasma potassium concentration when NO synthesis is reduced . Skinned coronary smooth muscle : calmodulin , calcium antagonists , and DB02527 influence contractility . The effects of Ca2+ , calmodulin , DB02527 , the catalytic subunit of DB02527 -dependent protein kinase ( CSU ) and some Ca2+ antagonists were studied in chemically ( Triton X-100 ) skinned coronary smooth muscle . P62158 increased the Ca2+ responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half-maximal activating Ca2+ concentration . DB00831 , a calmodulin antagonist , inhibited Ca2+-calmodulin-induced contraction . Both DB02527 and CSU were effective inhibitors of contraction induced at an intermediate Ca2+ concentration . DB08980 , a Ca2+-antagonist , at 2 x 10(-4) M produced a significant inhibitory effect , which was reduced by increasing the Ca2+ concentration . From other Ca2+ antagonists tested , W-7 , but not D600 and verapamil , produced some inhibitory effect . The data indicate that the response of skinned coronary smooth muscle to Ca2+ , calmodulin and DB02527 are similar to those obtained with other skinned smooth muscles . Furthermore , skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle . Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex . BACKGROUND : Cannabinoids have deleterious effects on prefrontal cortex ( P27918 ) -mediated functions and multiple evidences link the endogenous cannabinoid ( endocannabinoid ) system , cannabis use and schizophrenia , a disease in which P27918 functions are altered . Nonetheless , the molecular composition and the physiological functions of the endocannabinoid system in the P27918 are unknown . METHODOLOGY/PRINCIPAL FINDINGS : Here , using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the P27918 : presynaptic cannabinoid P21554 receptors ( CB1R ) faced postsynaptic P41594 while diacylglycerol lipase alpha ( Q9Y4D2 ) , the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol ( 2-AG ) was expressed in the same dendritic processes as P41594 . Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents . Prolonged synaptic stimulation at 10Hz induced a profound long-term depression ( LTD ) of layers V/VI excitatory inputs . The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic P41594 , phospholipase C and a rise in postsynaptic Ca(2+) as predicted from the localization of the different components of the endocannabinoid system . Blocking the degradation of 2-AG ( with Q76M96 602 ) but not of anandamide ( with Q76M96 597 ) converted subthreshold tetanus to LTD-inducing ones . Moreover , inhibiting the synthesis of 2-AG with DB01083 , blocked endocannabinoid-mediated LTD . All together , our data show that 2-AG mediates LTD at these synapses . CONCLUSIONS/SIGNIFICANCE : Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the P27918 . Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of P27918 -related pathologies . Inactivation of caspase-1 in rodent brain : a novel anticonvulsive strategy . PURPOSE : Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures . We previously found that intracerebral administration of interleukin-1 ( IL-1 ) -beta has proconvulsant effects , whereas its endogenous receptor antagonist ( IL-1Ra ) mediates potent anticonvulsant actions in various models of limbic seizures . In this study , we investigated whether seizures can be effectively inhibited by blocking the brain production of IL-1beta , by using selective inhibitors of interleukin-converting enzyme ( ICE/caspase-1 ) or through caspase-1 gene deletion . METHODS : P29466 was selectively blocked by using pralnacasan or DB05507 . IL-1beta release was induced in mouse organotypic hippocampal slice cultures by proinflammatory stimuli [ lipopolysaccharide ( LPS ) + adenosine triphosphate ( DB00171 ) ] and measured with enzyme-linked immunosorbent assay ( ELISA ) . IL-1beta production during seizures was measured in the rat hippocampus by Western blot . Seizures were induced in freely moving mice and rats by intrahippocampal injection of kainic acid and recorded by EEG analysis . RESULTS : P29466 inhibition reduced the release of IL-1beta in organotypic slices exposed to LPS+ DB00171 . Administration of pralnacasan ( intracerebroventricular , 50 microg ) or DB05507 ( intraperitoneal , 25-200 mg/kg ) to rats blocked seizure-induced production of IL-1beta in the hippocampus , and resulted in a twofold delay in seizure onset and 50 % reduction in seizure duration . Mice with caspase-1 gene deletion showed a 70 % reduction in seizures and an approximate fourfold delay in their onset . CONCLUSIONS : Inhibition of caspase-1 represents an effective and novel anticonvulsive strategy , which acts by selectively reducing the brain availability of IL-1beta . P21554 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome . The cannabinoid receptors , P21554 and CB2 , are expressed in the heart , but their role under pathological conditions remains controversial . This study examined the effect of P21554 receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome . MI was induced in Wistar rats by permanent ligation of the left coronary artery . Treatment with the P21554 receptor antagonist rimonabant ( 10 mg/kg i.p. daily ) started 7 days before or 6 h after MI and continued for 6 weeks . Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter . P21554 blockade improved systolic and diastolic heart function , decreased cardiac collagen and hydroxyproline content and down-regulated TGF-β1 . Additionally , rimonabant decreased arterial stiffness , normalised QRS complex duration and reduced brain natriuretic peptide levels in serum . In primary cardiac fibroblasts , rimonabant decreased P14780 activity and TGF-β1 expression . Furthermore , rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain . Blocking of P21554 receptor with rimonabant improves cardiac functions in the early and late stages after MI , decreases arterial stiffness and reduces cardiac remodelling . DB06155 also has cardioprotective actions in rats characterised by the metabolic syndrome . Inhibition of proteolysis and TGF-β1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI . Administration of adenosine diphosphate-ribosyl transferase antagonist allows in vivo control of anti-dinitrophenyl response . DB03073 ( 3MB ) is one of a series of chemical inhibitors of the nuclear enzyme adenosine diphosphate ( ADP ) -ribosyl transferase ( P09874 ) , which has been shown to inhibit cell differentiation in vitro , but has no effect on differentiation independent proliferation . Treatment of mice with an optimal concentration of 3MB ( 20 mg/kg body weight ) at or 1 day after dinitrophenyl-keyhole limpet haemocyanin ( DNP-KLH ) immunisation reduced anti-DNP plaque-forming cell ( P27918 ) numbers to less than 10 % of those of control animals . The period for maximum P27918 suppression showed a narrow time window relative to immunisation , suggesting that in vivo , as in vitro , 3 MB was acting only on those lymphocytes differentiating in response to antigen . Experimental findings showed that it was possible to select for P27918 derived from different populations of DNP-responsive lymphocytes by adjusting the time of 3MB treatment relative to immunisation . When 3MB was used with antigen priming , the residual P27918 showed a lower average affinity than P27918 in mice treated with 3MB 3 days after priming , suggesting a differential selection of those lymphocytes responding either ' early ' or ' late ' in the primary immune response . DB05387 ( AEterna ) . AEterna is developing DB05387 , an angiogenesis inhibitor derived from the ultrafiltration of liquid shark cartilage , with matrix metalloprotease ( MMP ) -2 , P14780 and vascular endothelial growth factor inhibitory properties , for the potential treatment of non-small-cell lung cancer . P29466 and caspase-8 cleave and inactivate cellular parkin . Lesions in the parkin gene cause early onset Parkinson 's disease by a loss of dopaminergic neurons , thus demonstrating a vital role for parkin in the survival of these neurons . O60260 is inactivated by caspase cleavage , and the major cleavage site is after Asp126 . Caspases responsible for parkin cleavage were identified by several experimental paradigms . Transient coexpression of caspases and wild type parkin in P29320 -293 cells identified caspase-1 , -3 , and -8 as efficient inducers of parkin cleavage whereas caspase-2 , -7 , -9 , and -11 did not induce cleavage . A D126A parkin mutation abrogates cleavage induced by caspase-1 and -8 , but not by caspase-3 . In anti-Fas-treated Jurkat T cells , parkin cleavage was inhibited by caspase inhibitors hFlip and CrmA ( but not by X-linked inhibitor of apoptosis ( P98170 ) ) , indicating that caspase-8 ( but not caspase-3 ) is responsible for the parkin cleavage in this model . Moreover , induction of apoptosis in caspase-3-deficient MCF7 cells , either by caspase-1 or -8 overexpression or by tumor necrosis factor-alpha treatment , led to parkin cleavage . These results demonstrate that caspase-1 and -8 can directly cleave parkin and suggest that death receptor activation and inflammatory stress can cause loss of the ubiquitin ligase activity of parkin , thus causing accumulation of toxic parkin substrates and triggering dopaminergic cell death . DB08901 is active against imatinib-resistant mutants of Q6UN15 - P16234 and P10721 , and against P11362 -derived fusion kinases . Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors . We have recently shown that the mu-opioid receptor [ P35372 , also termed mu-opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid-specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co-expressing P35372 and O14939 , treatment with ( D-Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C-terminal splice variant of the mu-opioid receptor ( MOR1D , also termed MOP(1D) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist-independent ( constitutive ) O14939 -activation facilitating agonist-induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over-expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta-opioid receptor [ Q8IXH6 , also termed delta-opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 -dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor ( GPCR ) endocytosis . 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 . Safety profile of maraviroc in patients coinfected with HIV-1 and hepatitis B or C included in the maraviroc expanded access program . OBJECTIVE : To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV-1 coinfected with hepatitis B virus ( HBV ) or hepatitis C virus ( HCV ) . METHODS : This was a multicenter , noncomparative , open-label , expanded access program ( EAP ) initiated in February 2007 . Patients with P51681 -tropic HIV-1 and HIV-1 RNA ≥ 1000 copies/mL on their current treatment received maraviroc 300 mg ( 150 mg with protease inhibitors ) twice daily with optimized background therapy ( OBT ) , which could include the newer agents raltegravir , etravirine , and darunavir . The adverse event ( AE ) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2 , where the OBT did not include these agents . RESULTS : A total of 1,032 patients were enrolled : 51 HIV/HBV coinfected ; 149 HIV/HCV coinfected , 9 HIV/HBV/HCV coinfected , and 823 HIV-1 monoinfected . Most ( 76 % ) received at least 1 newer agent . Overall AE frequency was comparable across coinfection groups ( 63 % -72 % ) . Hepatobiliary events were more common in HIV/HCV coinfection than in HIV monoinfection or HIV/HBV coinfection ( 10.0 , 4.8 , and 3.1 per 100 patient-years , respectively ) . Across all coinfection groups , there was a trend toward lower exposure-adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies . Grade 3/4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm . CONCLUSION : DB04835 plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV-1-infected patients coinfected with HBV or HCV . Cannabinoid 1 receptor-dependent transactivation of fibroblast growth factor receptor 1 emanates from lipid rafts and amplifies extracellular signal-regulated kinase 1/2 activation in embryonic cortical neurons . G-protein coupled receptors may mediate their effects on neuronal growth and differentiation through activation of extracellular signal-regulated kinases 1/2 ( P27361 /2 ) , often elicited by transactivation of growth factor receptor tyrosine kinases . This elaborate signaling process includes inducible formation and trafficking of multiprotein signaling complexes and is facilitated by pre-ordained membrane microdomains , in particular lipid rafts . In this study , we have uncovered novel signaling interactions of cannabinoid receptors with fibroblast growth factor receptors , which depended on lipid rafts and led to P27361 /2 activation in primary neurons derived from chick embryo telencephalon . More specifically , the cannabinoid 1 receptor ( CB1R ) agonist methanandamide induced tyrosine phosphorylation and transactivation of fibroblast growth factor receptor (FGFR)1 via Src and Fyn , which drove an amplification wave in P27361 /2 activation . Transactivation of P11362 was accompanied by the formation of a protein kinase C ε-dependent multiprotein complex that included CB1R , Fyn , Src , and P11362 . Recruitment of molecules increased with time of exposure to methanandamide , suggesting that in addition to signaling it also served trafficking of receptors . Upon agonist stimulation we also detected a rapid incorporation of CB1R , as well as activated Src and Fyn , and P11362 in lipid rafts . Most importantly , lipid raft integrity was a pre-requisite for CB1R-dependent complex formation . Our data provide evidence that lipid rafts may organize P21554 receptor proximal signaling events , namely activation of Src and Fyn , and transactivation of P11362 towards activation of P27361 /2 and induction of neuronal differentiation . Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents . Given that receptor tyrosine kinases ( RTKs ) have emerged as key regulators of all aspects of cancer development , including proliferation , invasion , angiogenesis and metastasis , the RTK family represents an important therapeutic target for anti-cancer drug development . Oxindole structure has been used in RTK inhibitors such as DB02058 and intedanib . In this study , two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized , and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated . Among them , compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC50s below 10μM . Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/ P55008 phase . Although the leading compounds DB02058 and intedanib targets P11362 , the kinase activity test revealed that these compounds only showed slight inhibitory activity on P11362 kinase . Further enzymatic test aided by molecular docking simulation in the DB00171 -binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase . These compounds are worthy of further evaluation as anticancer agents . Inhibition of cyclooxygenase-2 elicits a P21554 -mediated decrease of excitatory transmission in rat P00915 hippocampus . Cannabinoid receptor ( P21554 ) ligands decrease excitatory and inhibitory transmission in the hippocampus , but the influence of endogenously formed cannabinoids ( eCBs ) on basal excitatory transmission remains uncertain . Here , we investigated the influence of eCBs on synaptic transmission in P00915 hippocampus using the slice preparation . Blockade of P21554 with the selective receptor antagonists SR141716 ( rimonabant ) or AM251 augmented synaptic responses evoked upon stimulation of the Schaffer collaterals . This effect persisted in the presence of bicuculline or CGP55845 to block GABA(A) or GABA(B) receptors , revealing a tonic eCB influence on excitatory transmission . Selective inhibition of cyclooxygenase-2 ( P35354 ) with meloxicam or NS-398 decreased excitatory responses partly in a P21554 -dependent manner , independently of GABA(A) transmission . Paired-pulse paradigms suggested a presynaptic P21554 mechanism to decrease glutamate release . Inhibition of P23219 or other routes of eCB degradation did not affect synaptic transmission . We conclude that P35354 regulates the formation of P21554 ligands that decrease hippocampal excitatory transmission . Δ(9)- DB00470 treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection . The major psychoactive component of marijuana , Δ(9)-tetrahydrocannabinol ( THC ) , also acts to suppress inflammatory responses . Receptors for THC , P21554 , CB2 , and Q9Y2T6 , are differentially expressed on multiple cell types including monocytes and macrophages , which are important modulators of inflammation in vivo and target cells for HIV-1 infection . Use of recreational and medicinal marijuana is increasing , but the consequences of marijuana exposure on HIV-1 infection are unclear . Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation . THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle P51681 using viruses . In contrast , treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection . Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2 . THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell , while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle . Cells treated during differentiation with THC displayed reduced expression of P08571 , CD16 , and Q86VB7 and donor dependent increases in mRNA expression of selected viral restriction factors , suggesting a fundamental alteration in phenotype . Ultimately , the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor ( P01730 , P51681 and P61073 ) expression that diminished entry efficiency .