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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
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PMID:International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. 1203 35

Although Delta(9)-tetrahydrocannabinol (THC) produces analgesia, its effects on nociceptive primary afferents are unknown. These neurons participate not only in pain signaling but also in the local response to tissue injury. Here, we show that THC and cannabinol induce a CB(1)/CB(2) cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves. Other psychotropic cannabinoids cannot mimic this action. The vanilloid receptor antagonist ruthenium red abolishes the responses to THC and cannabinol. However, the effect of THC on sensory nerves is intact in vanilloid receptor subtype 1 gene knock-out mice. The THC response depends on extracellular calcium but does not involve known voltage-operated calcium channels, glutamate receptors, or protein kinases A and C. These results may indicate the presence of a novel cannabinoid receptor/ion channel in the pain pathway.
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PMID:Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. 1204 79

In canine renal tubular cells, effect of olvanil, a presumed cannabinoid and vanilloid receptor modulator, on intracellular Ca2+ concentration ([Ca2+]i) was measured by using fura-2. Olvanil (5-100 microM) caused a rapid and sustained [Ca2+]i rise in a concentration-dependent manner. Olvanil-induced [Ca2+]i rise was prevented by 70 and 90% by removal of extracellular Ca2+ and La3+, respectively, but was not changed by dihydropyridines, verapamil and diltiazem. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of olvanil on [Ca2+]i was abolished; also, pretreatment with olvanil partly reduced thapsigargin-induced [Ca2+]i rise. U73122, an inhibitor of phoispholipase C, abrogated ATP-, but partly inhibited olvanil-, induced [Ca2+]i rise. Two cannabinoid receptor antagonists (AM251 and AM281; 5 microM) and a vanilloid receptor antagonist (capsazepine; 100 microM) did not alter olvanil (50 microM)-induced [Ca2+]i rise. These results suggest that olvanil rapidly increases [Ca2+]i in renal tubular cells, by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release via mechanism(s) independent of stimulation of cannabinoid and vanilloid receptors.
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PMID:Effect of olvanil (N-vanillyl-cis-9-octadecenoamide) on cytosolic Ca2+ increase in renal tubular cells. 1240 75

Endogenous cannabinoids (endocannabinoids) are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to both inhibitory ["depolarization-induced suppression of inhibition" (DSI)] and excitatory ("depolarization-induced suppression of excitation") afferent fibers. Transient endocannabinoid release is triggered by voltage-dependent Ca(2+) influx and is upregulated by group I metabotropic glutamate receptor activation. Here we show that muscarinic acetylcholine receptor (mAChR) activation also enhances transient endocannabinoid release (DSI) and induces persistent release. Inhibitory synapses in the rat hippocampal CA1 region of acute slices were studied using whole-cell patch-clamp techniques. We found that low concentrations (0.2-0.5 microm) of carbachol (CCh) enhanced DSI without affecting basal evoked IPSCs (eIPSCs) by activating mAChRs on postsynaptic cells. Higher concentrations of CCh (> or =1 microm) enhanced DSI and also persistently depressed basal eIPSCs, mainly by releasing endocannabinoids. Persistent CCh-induced endocannabinoid release did not require an increase in [Ca2+]i but was dependent on G-proteins. Although they were independent at the receptor level, muscarinic and glutamatergic mechanisms of endocannabinoid release shared intracellular machinery. Replication of the effects of CCh by blocking acetylcholinesterase with eserine suggests that mAChR-mediated endocannabinoid release is physiologically relevant. This study reveals a new role of the muscarinic cholinergic system in mammalian brain.
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PMID:Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. 1245 Nov 19

Palmitoylethanolamide (PEA) is a bioactive fatty acid amide belonging to the class of N-acyl-ethanolamines (NAEs). This compound has been known since the 1950s for its anti-inflammatory effects, but was re-discovered only after the finding that another NAE, arachidonoyl-ethanolamide (anandamide, AEA), could act as an endogenous ligand of cannabinoid receptors. Although a similar function for PEA has also been proposed, this compound does not activate the two cannabinoid receptor subtypes described to date. PEA and AEA are co-synthesized by cells, and PEA might act as an 'entourage' compound for AEA, i.e. as an endogenous enhancer of AEA biological actions. Indeed, long-term treatment of human breast cancer cells (HBCCs) with PEA downregulates the expression of the enzyme responsible for AEA degradation, the fatty acid amide hydrolase, thereby leading to an enhancement of AEA-induced, and cannabinoid CB1 receptor-mediated, cytostatic effect on HBCCs. AEA is also a full agonist for the receptors of another class of bioactive fatty acid amides, the N-acyl-vanillyl-amines (e.g. capsaicin and olvanil). These sites of action are known as vanilloid receptors of type 1 (VR1). PEA enhances the VR1-mediated effects of AEA and capsaicin on calcium influx into cells. These 'entourage' effects of PEA might be attributable to modulation of VR1 activity, and could underlie the enhancement by PEA, described here for the first time, of the antiproliferative effects of VR1 receptor agonists.
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PMID:Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signalling systems. 1257 18

A key role for DAG lipase activity in the control of axonal growth and guidance in vitro and in vivo has been established. For example, DAG lipase activity is required for FGF-stimulated calcium influx into neuronal growth cones, and this response is both necessary and sufficient for an axonal growth response. The mechanism that couples the hydrolysis of DAG to the calcium response is not known. The initial hydrolysis of DAG at the sn-1 position (by DAG lipase) will generate 2-arachidonylglycerol, and this molecule is well established as an endogenous cannabinoid receptor agonist in the brain. In the present paper, we show that in rat cerebellar granule neurons, CB1 cannabinoid receptor antagonists inhibit axonal growth responses stimulated by N-cadherin and FGF2. Furthermore, three CB1 receptor agonists mimic the N-cadherin/FGF2 response at a step downstream from FGF receptor activation, but upstream from calcium influx into cells. In contrast, we could find no evidence for the CB1 receptor coupling the TrkB neurotrophin receptor to an axonal growth response in the same neurons. The observation that the CB1 receptor can couple the activated FGF receptor to an axonal growth response raises novel therapeutic opportunities.
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PMID:The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. 1257 7

Cannabinoid CB1 receptors have been detected in retinas of numerous species, with prominent labeling in photoreceptor terminals of the chick and monkey. CB1 labeling is well-conserved across species, suggesting that CB1 receptors might also be present in photoreceptors of the tiger salamander. Synaptic transmission in vertebrate photoreceptors is mediated by L-type calcium currents-currents that are modulated by CB1 receptors in bipolar cells of the tiger salamander. Presence of CB1 receptors in photoreceptor terminals would therefore be consistent with presynaptic modulation of synaptic transmission, a role seen for cannabinoids in other parts of the brain. Here we report immunohistochemical and electrophysiological evidence for the presence of functional CB1 receptors in rod and cone photoreceptors of the tiger salamander. The cannabinoid receptor agonist WIN 55212-2 enhances calcium currents of rod photoreceptors by 39% but decreases calcium currents of large single cones by 50%. In addition, WIN 55212-2 suppresses potassium currents of rods and large single cones by 44 and 48%, respectively. Thus functional CB1 receptors, present in the terminals of rod and cone photoreceptors, differentially modulate calcium and potassium currents in rods and large single cones. CB1 receptors are therefore well positioned to modulate neurotransmitter release at the first synapse of the visual system.
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PMID:Cannabinoid receptor activation differentially modulates ion channels in photoreceptors of the tiger salamander. 1274 Apr 9

The effect of the endogenous cannabinoid ligand anandamide on the function of the cloned alpha7 subunit of the nicotinic acetylcholine (ACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Anandamide reversibly inhibited nicotine (10 microM) induced-currents in a concentration-dependent manner (10 nM to 30 microM), with an IC50 value of 229.7 +/- 20.4 nM. The effect of anandamide was neither dependent on the membrane potential nor meditated by endogenous Ca2+ dependent Cl- channels since it was unaffected by intracellularly injected BAPTA and perfusion with Ca2+-free bathing solution containing 2 mM Ba2+. Anandamide decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on nicotinic acetylcholine (nACh) alpha7 receptors. This effect was not mediated by CB1 or CB2 receptors, as neither the selective CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) nor CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethyl-bicyclo-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528) reduced the inhibition by anandamide. In addition, inhibition of nicotinic responses by anandamide was not sensitive to either pertussis toxin treatment or to the membrane permeable cAMP analog 8-Br-cAMP (0.2 mM). Inhibitors of enzymes involved in anandamide metabolism including phenylmethylsulfonyl fluoride, superoxide dismutase, and indomethacin, or the anandamide transport inhibitor AM404 did not prevent anandamide inhibition of nicotinic responses, suggesting that anandamide itself acted on nicotinic receptors. In conclusion, these results demonstrate that the endogenous cannabinoid anandamide inhibits the function of nACh alpha7 receptors expressed in Xenopus oocytes in a cannabinoid receptor-independent and noncompetitive manner.
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PMID:The endogenous cannabinoid anandamide inhibits alpha7 nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. 1276 52

Effects of cannabinoids on endogenous potassium and calcium currents in HEK293 cells were studied using the whole-cell variant of the patch-clamp technique. The cannabinoid agonists WIN 55,212-2, methanandamide, and anandamide (1 microM) decreased the calcium current by 53.1 +/- 2.6, 47.5 +/- 1.2, and 38.8 +/- 3.1%, respectively, after transfection of human CB1 cannabinoid receptor (hCB1) cDNA into HEK293 cells. The delayed rectifier-like current was not changed after application of these agonists, but the inward rectifier was increased by 94.0 +/- 3.6, 83.7 +/- 5.1, and 63.0 +/- 2.5% after application of WIN 55,212-2, methanandamide, and anandamide, respectively. The effects of the cannabinoid antagonists (AM251, AM281, and AM630) on the inward rectifier and calcium currents were the opposite of those seen with cannabinoid agonists; thus, these compounds act as inverse agonists in this preparation. These results suggest that endogenous inward rectifier and calcium currents are modulated by cannabinoids in HEK293 cells, and that some expressed receptors may be constitutively active.
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PMID:Effects of cannabinoids on endogenous K+ and Ca2+ currents in HEK293 cells. 1277 49

(1) Three cannabinoid receptor agonists, anandamide (CB(1) receptor-selective) and the aminoalkyl-indoles, JWH 015(2-methyl-1-propyl-1H-indol-3-yl)-1-napthalenylmethanone; (CB(2) receptor-selective), R-(+)-WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; slightly CB(2) receptor-selective), as well as the enantiomer S-(-)-WIN 55,212-3(S-(-)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; inactive at cannabinoid receptors), induced endothelium-independent relaxation of methoxamine-precontracted isolated small mesenteric artery of rat. KCL (60 mM) precontraction did not affect relaxation to the aminoalkylindoles, but reduced that to anandamide. (2) SR14176A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 3 micro M; CB(1) receptor antagonist) inhibited relaxation only to JWH 015 and anandamide. Neither AM 251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; CB(1) antagonist) nor SR 144528 (N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; CB(2) antagonist; both at 3 micro M) affected any of the relaxations. (3) Vanilloid receptor desensitisation with capsaicin reduced anandamide relaxation; addition of SR 141716A (3 micro M) then caused further inhibition. SR 141716A did not affect capsaicin-induced relaxation. (4) The aminoalkylindoles inhibited CaCl(2)-induced contractions in methoxamine-stimulated vessels previously depleted of intracellular Ca(2+). These inhibitory effects were greatly reduced or abolished in ionomycin-(a calcium ionophore) contracted vessels. Anandamide also caused vanilloid receptor-independent, SR 141716A- (3 micro M) insensitive, inhibition of CaCl(2) contractions. (5) In conclusion, the aminoalkylindoles JWH 015, R-(+)-WIN 55,212-2 and S-(-)-WIN 55,212-3 relax rat small mesenteric artery mainly by inhibiting Ca(2+) influx into vascular smooth muscle. Anandamide causes vasorelaxation by activating vanilloid receptors, but may also inhibit Ca(2+) entry. Relaxation to JWH 015 and anandamide was sensitive to SR 141716A, but there is no other evidence for the involvement of CB(1) or CB(2) receptors in responses to these compounds.
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PMID:Endothelium-independent relaxation to cannabinoids in rat-isolated mesenteric artery and role of Ca2+ influx. 1278 18


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