Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling of the cannabinoid CB1 and CB2 receptors through phospholipase C (PLC) and G protein-coupled inwardly rectifying K+ channels (GIRK) was studied after their expression in COS7 cells and Xenopus oocytes. The CB1 or CB2 receptor was co-expressed with alpha subunits of the Galphaq family (Galphaq, Galpha11, Galpha14, Galpha15 and Galpha16) in COS7 cells. Receptor-dependent activation of PLC was observed after co-expressing the CB1 receptor with Galpha14, Galpha15 or Galpha16 but not with Galphaq or Galpha11. Co-expression of Gbeta1 and Ggamma2 abolished the activation, indicating that the activation was mediated by Galpha. PLC activation was not observed when the CB2 receptor was expressed alone or co-expressed with any of the above Galpha subunits. Coupling to GIRK was observed with both CB1 and CB2 receptors after expression in Xenopus oocytes. Significantly larger currents were induced when the receptor was co-expressed with both GIRK1 and GIRK4 than with either GIRK alone. Co-expression of Galpha transducin with the receptor significantly reduced the K+ currents, indicating that GIRK activation was mediated by Gbetagamma but not by Galpha. These findings suggest two new signaling pathways for the cannabinoid receptors.
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PMID:Coupling of the expressed cannabinoid CB1 and CB2 receptors to phospholipase C and G protein-coupled inwardly rectifying K+ channels. 1055 Dec 68

1. The effects of cannabinoid (CB) receptor stimulation on membrane currents in single cells from the Syrian hamster vas deferens cell line DDT1MF-2 were investigated using the whole cell patch clamp technique. 2. The CB receptor agonist CP55,940 evoked a concentration-dependent transient outward current. The selective CB1 receptor ligand SR141716 (1 microM), but not the selective CB2 receptor ligand SR144528 (1 microM), inhibited the outward current. Pertussis toxin (100 ng ml-1 for 20 h) completely abolished the outward current. 3. Western blotting with an antibody against the rat (r)CB1 receptor showed a band characteristic for the CB1 receptor around 63 kDa in DDT1MF-2 cells. 4. The reversal potential for the outward current measured using a voltage ramp protocol was -84 +/- 5 mV. The current was inhibited by the Ca2+-dependent K+ channel blockers iberiotoxin (10 nM) and charybdotoxin (10 nM). 5. Removal of Ca2+ from the bathing solution, or the addition of 0.1 mM Cd2+ completely abolished the outward current evoked by 10 microM CP55,940. 6. The sarcoplasmic Ca2+ pump inhibitor thapsigargin reduced the outward current evoked by 10 microM CP55,940 in a concentration-dependent manner. 7. The mitogen-activating protein kinase (MAP kinase) inhibitor PD98059, but not the phospholipase C inhibitor U73122, inhibited the outward current evoked by 10 microM CP55,940. 8. The adenylyl cyclase inhibitor SQ22,536 (100 microM) and 8-Br-cyclic AMP (10 microM) significantly reduced the outward current evoked by 10 microM CP55,940. 9. Our data suggest that CB1 receptor stimulation in DDT1MF-2 cells leads to activation of a large conductance Ca2+-dependent K+ channel through a Gi/Go protein-mediated rise in [Ca2+]i, for which both inhibition of adenylyl cyclase and activation of MAP kinase are required. In addition, the cannabinoid-induced increase in [Ca2+]i is likely to arise from capacitive Ca2+ entry.
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PMID:Signal transduction of cannabinoid CB1 receptors in a smooth muscle cell line. 1117 94

The effect of CP55,940, a presumed CB1/CB2 cannabinoid receptor agonist, on intracellular free Ca2+ levels ([Ca2+]i) in Madin-Darby canine kidney cells was examined by using the fluorescent dye fura-2 as a Ca2+ indicator. CP55,940 (2-50 microM) increased [Ca2+]i concentration-dependently with an EC50 of 8 microM. The [Ca2+]i signal comprised an initial rise and a sustained phase. Extracellular Ca2+ removal decreased the maximum [Ca2+]i signals by 32+/-12%. CP55,940 (20 microM)-induced [Ca2+]i signal was not altered by 5 microM of two cannabinoid receptor antagonists, AM-251 and AM-281. CP55,940 (20 microM)-induced [Ca2+]i increase in Ca2+-free medium was inhibited by 86+/-3% by pretreatment with 1 microM thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor. Conversely, pretreatment with 20 microM CP55,940 in Ca2+-free medium for 6 min abolished thapsigargin-induced [Ca2+]i increases. CP55,940 (20 microM)-induced intracellular Ca2+ release was not inhibited when inositol 1,4,5-trisphosphate formation was abolished by suppressing phospholipase C with 2 microM U73122. Collectively, this study shows that CP,55940 induced significant [Ca2+]i increases in canine renal tubular cells by releasing stored Ca2+ from the thapsigargin-sensitive pools in an inositol 1,4,5-trisphosphate-independent manner, and also by causing extracellular Ca2+ entry. The CP55,940's action appears to be dissociated from stimulation of cannabinoid receptors.
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PMID:CP55,940 increases intracellular Ca2+ levels in Madin-Darby canine kidney cells. 1155 15

The study was undertaken to explore the effect of CP55,940 ((-)-cis-3-[2-Hydroxy4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol), a drug commonly used as a CB1/CB2 cannabinoid receptor agonist, on intracellular free Ca2+ levels ([Ca2+]i) in several cell types [Ca2+]i was measured in suspended cells by using the fluorescent dye fura-2 as an indicator. At concentrations between 1-50 microM, CP55,940 increased [Ca2+]i in a concentration-dependent manner with an EC50 of 8 microM. The [Ca2+]i signal comprised an initial rise, a slow decay, and a sustained phase. CP55940 (10 microM)-induced (Ca2+]i signal was not altered by 5 microM of two cannabinoid receptor antagonists (AM-251, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM-281, 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-m3thyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide). Extracellular Ca2+ removal decreased the maximum value of the Ca2+ signals by 50%. CPS5,940 (10 microM)-induced [Ca2+]i increase in Ca2+-free medium was inhibited by 80% by pretreatment with 1 microM thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor. Conversely, pretreatment with 10 microM CP55,940 in Ca2+-free medium for 6 min abolished thapsigargin-induced [Ca2+]i increase. Nifedipine (10 microM) and verapamil (10 microM) did not alter CP55,940 (10 microM)-induced [Ca2+]i increase. CP55, 940 (10 microM)-induced Ca2+ release was not affected when phospholipase C was inhibited by 2 microM U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione). CP55,940 (5 microM) also increased [Ca22+] in Madin-Darby canine kidney cells, MG63 human osteosarcoma cells, and IMR-32 neuroblastoma cells. Collectively, CP,55940 induced significant [Ca2+]i increases in several cell types by releasing store Ca2+ from thapsigargin-sensitive pools and by causing Ca2+ entry. The CP55,940's action appears to be dissociated from stimulation of cannabinoid receptors
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PMID:Novel effect of CP55,940, a CB1/CB2 cannabinoid receptor agonist, on intracellular free Ca2+ levels in bladder cancer cells. 1200 50

The study was undertaken to explore the effect of CP55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol), a drug commonly used as a CB1/CB2 cannabinoid receptor agonist, on intracellular free Ca2+ levels ([Ca2+]i) in MG63 human osteoblast-like epithelial cells. [Ca2+]i was measured in suspended cells by using the fluorescent dye fura-2 as an indicator. At concentrations between 2-20 microM, CP55,940 increased [Ca2+]i in a concentration-dependent manner with an EC50 of 8 microM. The [Ca2+] signal comprised an initial rise, a slow decay, and a sustained phase. CP55940 (10 microM)-induced [Ca2+]i signal was not altered by 5 microM of two cannabinoid receptor antagonists (AM-251, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole3-carboxamide; AM-281, 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide). Extracellular Ca2+ removal decreased the maximum value of the Ca2+ signals by 50%. CP55,940 induced quench of fura-2 fluorescence by Mn2+ (50 microM), suggesting the presence of Ca2+ influx across the plasma membrane. CP55,940 (10 microM)-induced [Ca2+]i increase in Ca(2+)-free medium was inhibited by 84% by pretreatment with 1 microM thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor. Conversely, pretreatment with 10 microM CP55,940 in Ca(2+)-free medium abolished thapsigargin-induced [Ca2+]i increase. At 1 microM, nifedipine, verapamil, and diltiazem did not alter CP55, 940 (10 microM)-induced [Ca2+]i increase. CP55,940 (20 microM)-induced Ca2+ release was not affected when phospholipase C was inhibited by 2 microM U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino) hexyl)-1H-pyrrole-2,5-dione). CP55,940 (20 microM) did not induce acute cell death after incubation for 30 min as assayed by trypan blue exclusion. Collectively, CP55,940 induced significant [Ca2+]i increases in osteoblasts by releasing store Ca2+ from thapsigargin-sensitive stores and by causing Ca2+ entry. The CP55,940's action appears to be independent of stimulation of CB1 cannabinoid receptors.
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PMID:Effect of (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55,940) on intracellular Ca2+ levels in human osteosarcoma cells. 1281 11

The endocannabinoid anandamide has been reported to affect neuronal cells, immune cells and smooth muscle cells via either CB1 or CB2 receptors. In endothelial cells, the receptors involved in activating signal transduction are still unclear, despite the fact that anandamide is produced in this cell type. The present study was designed to explore in detail the effect of this endocannabinoid on Ca2+ signaling in single cells of a calf pulmonary endothelial cell line. Anandamide initiated a transient Ca2+ elevation that was prevented by the CB2 receptor antagonist SR144528, but not by the CB1 antagonist SR141716A. These data were confirmed by molecular identification of the bovine CB2 receptor in these endothelial cells by partial sequencing. The phospholipase C inhibitor 1-[6-[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5dione and the inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenylborate prevented Ca2+ signaling in response to anandamide. Using an improved cameleon probe targeted to the endoplasmic reticulum (ER), fura-2 and ratiometric-pericam, which is targeted to the mitochondria, anandamide was found to induce Ca2+ depletion of the ER accompanied by the activation of capacitative Ca2+ entry (CCE) and a transient elevation of mitochondrial Ca2+. These data demonstrate that anandamide stimulates the endothelial cells used in this study via CB2 receptor-mediated activation of phospholipase C, formation of inositol 1,4,5-trisphosphate, Ca2+ release from the ER and subsequent activation of CCE. Moreover, the cytosolic Ca2+ elevation was accompanied by a transient Ca2+ increase in the mitochondria. Thus, in addition to its actions on smooth muscle cells, anandamide also acts as a powerful stimulus for endothelial cells.
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PMID:Anandamide initiates Ca(2+) signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. 1464 43

In this study, we have determined the contractile effects of CB1 and CB2 cannabinoid receptor activation on rat isolated atria and the different signaling pathways involved. Anandamide did not has significantly effect on atria contractility, however, the treatment with both CB1 (AM251) or CB2 (AM630) receptor antagonists, the endocannabinoids triggered stimulation or inhibition on contractility respectively. The ACEA stimulation of CB1 receptor exerted decrease on contractility, that significantly correlated with the decrement of cAMP and the stimulation of nitric oxide synthase (NOS) and the accumulation of cyclic GMP (cGMP). On the contrary, JWH 015 stimulation of CB2 receptor triggered positive contractile response that significantly correlated with the increase cAMP production. The inhibiton of adenylate cyclase activity impaired the JWH 015 activation of CB1 receptor induced positive contractile effect, while inhibitors of phospholipase C (PLC), NOS and soluble nitric oxide (NO)-sensitive guanylate cyclase blocked the dose-response curves of ACEA on contractility. Those inhibitors also attenuated the CB1 receptor-dependent increase in activation of NOS and cGMP accumulation. These results suggest that CB2 receptor agonist mediated positive contractile effect associated with increased production on cAMP while CB1 receptor agonist mediated decrease on contractility associated with decreased cAMP accumulation and increase production of NO and cGMP; that occur secondarily to stimulation of PLC, NOS and soluble guanylate cyclase. Data give pharmacological evidence for the existence of functional CB1 and CB2 cannabinoid receptors in rat isolated atria and may contribute to a better understanding the effects of cannabinoids in the cardiovascular system.
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PMID:Differential CB1 and CB2 cannabinoid receptor-inotropic response of rat isolated atria: endogenous signal transduction pathways. 1588 56

Cannabinoids (CBs) exert untoward effects on reproduction by reducing LH secretion and suppressing gonadal function. Recent evidence suggests these effects are due primarily to hypothalamic dysfunction; however, the mechanism is obscure. Using immortalized hypothalamic GnRH neurons, we find these cells produce and secrete at least two different endocannabinoids. After release, 2-arachidonyl monoacylglycerol and anandamide are rapidly transported into GnRH neurons and are degraded to other lipids by fatty-acid amide hydrolase. The immortalized GnRH neurons also possess CB1 and CB2 receptors that are coupled to Gi/Go proteins whose activation leads to inhibition of GnRH secretion. In perifusion experiments, CBs block pulsatile release of GnRH. When a CB receptor agonist is delivered into the third ventricle of adult female mice, estrous cycles are prolonged by at least 2 d. Although in situ hybridization experiments suggest either that GnRH neurons in vivo do not possess CB1 receptors or that they are very low, transcripts are localized in close proximity to these neurons. Inasmuch as GnRH neurons in vivo possess G protein receptors that are coupled to phospholipase C and increased intracellular Ca2+, these same neurons should also be able to synthesize endocannabinoids. These lipids, in turn, could bind to CB receptors on neighboring cells, and perhaps GnRH neurons, to exert feedback control over GnRH function. This network could serve as a novel mechanism for regulating GnRH secretion where reproductive functions as diverse as the onset of puberty, timing of ovulation, duration of lactational infertility, and initiation/persistence of menopause may be affected.
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PMID:Regulation of gonadotropin-releasing hormone secretion by cannabinoids. 1602 Apr 80

GPR55 has recently attracted much attention as another member of the cannabinoid family, potentially explaining physiological effects that are non-CB1/CB2 mediated. However, the data gathered so far are conflicting with respect to its pharmacology. We review the primary literature to date on GPR55, describing its discovery, structure, pharmacology and potential physiological functions. The CB1 receptor antagonist/inverse agonist AM251 has been shown to be a GPR55 agonist in all reports in which it was evaluated, as has the lysophospholipid, lysophosphatidylinositol (LPI). Whether GPR55 responds to the endocannabinoid ligands anandamide and 2-arachidonylglycerol and the phytocannabinoids, delta-9-tetrahydrocannabidiol and cannabidiol, is cell type and tissue-dependent. GPR55 has been shown to utilize G(q), G(12), or G(13) for signal transduction; RhoA and phospholipase C are activated. Experiments with mice in which GPR55 has been inactivated reveal a role for this receptor in neuropathic and inflammatory pain as well as in bone physiology. Thus delineating the pharmacology of this receptor and the discovery of selective agonists and antagonists merits further study and could lead to new therapeutics.
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PMID:Pharmacological characterization of GPR55, a putative cannabinoid receptor. 2029 15

The endocannabinoid system and endocannabinoid receptor-driven modulation of glutamate release were studied in rat brain cortex astroglial gliosomes. These preparations contained the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, as well their major biosynthetic (N-acyl-phosphatidylethanolamines-hydrolyzing-phospholipase D and diacylglycerol-lipase) and catabolic (fatty acid amide-hydrolase and monoacylglycerol-lipase) enzymes. Gliosomes expressed type-1 (CB1R), type-2 (CB2R) cannabinoid, and type-1 vanilloid (TRPV1) receptors, as ascertained by Western blotting and confocal microscopy. Methanandamide, a stable analogue of anandamide acting as CB1R, CB2R, and TRPV1 agonist, stimulated or inhibited the depolarization-evoked gliosomal [(3)H]D: -aspartate release, at lower and higher concentrations, respectively. Experiments with ACEA (arachidonyl-2'-chloroethylamide), JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]-pyran) and capsaicin, selective agonists at CB1R, CB2R and TRPV1, respectively, demonstrated that potentiation of [(3)H]D: -aspartate release was due to CB1R while inhibition to CB2R and TRPV1 engagement. These findings were confirmed by using selective receptor antagonists. Furthermore, CB1R activation caused increase of intracellular IP3 and Ca(2+) concentration, suggesting an involvement of phospholipase C.
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PMID:The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate release. 2071 16


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