Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat brain cannabinoid receptor (CB-1) was stably transfected into the murine tumor line AtT-20 to study its coupling to inwardly rectifying potassium currents (Kir) and high voltage-activated calcium currents (ICa). In cells expressing CB-1 ("A-2" cells), cannabinoid agonist potently and stereospecifically activated Kir via a pertussis toxin-sensitive G protein. ICa in A-2 cells was sensitive to dihydropyridines and omega CTX MVIIC, less so to omega CgTX GVIA and insensitive to omega Aga IVa. In CB-1 expressing cells, cannabinoid agonist inhibited only the omega CTX MVIIC-sensitive component of ICa. Inhibition of Q-type ICa was voltage dependent and PTX sensitive, thus similar in character to the well-studied modulation of N-type ICa. An endogenous cannabinoid, anandamide, activated Kir and inhibited ICa as efficaciously as potent cannabinoid agonist. Immunocytochemical studies with antibodies specific for class A, B, C, D, and E voltage-dependent calcium channel alpha 1 subunits revealed that AtT-20 cells express each of these major classes of alpha 1 subunit.
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PMID:Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. 747 17

Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (IA) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on IA. The specific issue of whether cannabinoid receptor modulation of voltage-dependent IA acts via a cAMP-dependent process was investigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cyclase stimulant forskolin, produced concentration-dependent shifts in IA that were opposite those produced by cannabinoid receptor ligands. Moreover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also produced a marked negative shift in the steady-state voltage dependence of IA and increased the effect of forskolin on IA. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased IA via a decrease in steady-state voltage-dependent inactivation of IA. WIN 55,212-2 also reversed the effects of forskolin on IA. The electrophysiological studies were paralleled by direct assays of cAMP in these cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that pertussis toxin-sensitive cannabinoid receptor-mediated changes in IA were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of IA conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.
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PMID:Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process. 753 81

The recently cloned CB2 cannabinoid receptor subtype was stably transfected into AtT-20 and Chinese hamster ovary cells to compare the binding and signal transduction properties of this receptor with those of the CB1 receptor subtype. The binding of [3H]CP 55,940 to both CB1 and CB2 was of similar high affinity (2.6 and 3.7 nM, respectively) and saturable. In competitive binding experiments, (-)-delta 9-tetrahydrocannabinol and CP 55,940 were equipotent at the CB1 and CB2 receptors, but WIN 55212-2 and cannabinol bound with higher affinity to the CB2 than the CB1 receptor. HU 210 had a higher affinity for the CB1 receptor. Anandamide, a recently identified endogenous cannabinoid agonist, was essentially equipotent at both receptor subtypes. The structurally related fatty acid ethanolamides dihomo-gamma-linolenylethanolamide and mead ethanolamide also bound with relatively equal affinity to both receptors, but adrenylethanolamide had a higher affinity for the CB1 receptor. The rank order of potency and efficacy for binding of the selected agonists to the CB1 and CB2 receptors was mimicked in functional inhibition of cAMP accumulation experiments for all compounds tested. Both CB1 and CB2 receptors couple to the inhibition of cAMP accumulation that was pertussis toxin sensitive. SR141716A, a CB1 receptor antagonist, was a poor antagonist at the CB2 receptor in both binding and functional inhibition of cAMP accumulation experiments. When expressed in AtT-20 cells, the CB1 receptor mediated an inhibition of Q-type calcium channels and an activation of inward rectifying potassium channels. In contrast, the CB2 receptor did not modulate the activity of either channel under identical assay conditions. Similar to results obtained for CB1 receptor, the CB2 receptor did not couple to the activation of phospholipases A2, C, or D or to the mobilization of intracellular Ca2+. Except for its inability to couple to the modulation of Q-type calcium channels or inwardly rectifying potassium channels, the CB1 and CB2 receptors display similar pharmacological and biochemical properties.
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PMID:Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. 756 24

Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (IA) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of IA. Specific activators of PKA produced a negative shift in voltage dependence of IA, whereas PKA inhibitors produced a positive shift in IA voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in IA induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in IA voltage dependence. This partial effect of PKA inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of IA.
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PMID:Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium "A-current" in cultured rat hippocampal neurons. 777 35

The neuronal cannabinoid receptor clone was expressed of saturable [3H]WIN 55,212-2 binding sites. Co-expression of the cannabinoid receptor with cRNA coding for the G-protein-gated inwardly rectifying K+ channel (GIRK1) resulted in oocytes exhibiting large inward K+ currents in response to the cannabinoid agonist WIN 55,212-2. The activation of the potassium current by WIN 55,212-2 was dose-dependent with an EC50 of 630 nM. These results suggest that activation of inwardly rectifying K+ channels may be an additional effector mechanism for brain cannabinoid receptors.
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PMID:Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. 777 6

Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significance. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, levonantradol and WIN 55,212-2) on cultured neurons from hippocampus, a brain region that exhibits high cannabinoid receptor density. The electrophysiological effects of cannabinoids were determined by whole-cell patch clamp recordings of voltage-dependent potassium currents. The voltage dependence of the rapidly inactivating potassium A current (IA), characteristic of hippocampal neurons, was significantly altered in a concentration-dependent manner by cannabinoid analogs. Decreased inactivation, which led to an increased activation of IA near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on IA while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid analogs was similar to that observed with respect to binding at cannabinoid receptors in brain membranes. The concentration-related effectiveness of cannabinoid analogs in modulating IA was similar to their potency in stimulating low Km GTPase in cell membranes isolated from the cannabinoid receptor-rich dentate gyrus. These data support the conclusion that cannabinoid effects on IA are mediated through G-protein-coupled receptors. This cannabinoid-induced shift in the voltage dependence of IA could serve to counteract fast, transient, depolarizing events such as action potentials and synaptic currents in hippocampal neurons.
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PMID:Cannabinoids modulate potassium current in cultured hippocampal neurons. 808 16

The recent discovery and cloning of cannabinoid receptors has provided a major breakthrough in the understanding of the biochemical mechanisms of action of delta 9-tetrahydrocannibinol (delta 9-THC). Cannabinoid receptors are coupled to G-proteins and inhibit adenylyl cyclase in a variety of systems. In the brain, cannabinoid-inhibited adenylyl cyclase and the receptors are particularly prevalent in the cerebellum, where they are localized to cerebellar granule cells (Fig. 1). In these cells, cannabinoid receptors are co-localized with other Gi/o-linked receptors such as gamma-aminobutyric acid (GABAB) receptors, where they share common effector systems (adenylyl cyclase catalytic units) but not common G-proteins. This sharing of effectors leads to the phenomenon of receptor convergence, in which agonists of different receptor types can produce the same biological response in certain cells. In cultured hippocampal neurons, cannabinoids also act through G-proteins to increase potassium conductance. In these cells, the predominant electrophysiological response at relatively low (microM) concentrations of cannabinoids is mediated through a voltage-sensitive potassium A current (IA) (Fig. 1). The action of cannabinoid receptors in this system is to shift the voltage sensitivity of IA channels to higher voltage ranges, thus increasing K+ conductance at lower membrane potentials and decreasing the probability of multiple action potentials. When combined with data from other groups showing a cannabinoid receptor-mediated decrease in calcium conductance, along with the unique localization of cannabinoid receptors in the brain, it is clear that these receptor-effector combinations are well situated to mediate many of the well-known neurobiological effects of delta 9-THC.
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PMID:Cannabinoid receptors: G-protein-mediated signal transduction mechanisms. 819 87

Anandamide has been identified in porcine brain as an endogenous cannabinoid receptor ligand and is believed to be a counterpart to the psychoactive component of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC). Here we report that anandamide directly inhibits (IC50, 2.7 muM) Shaker-related Kv1.2 K+ channels that are found ubiquitously in the mammalian brain. Delta 9-THC also inhibited Kv1.2 channels with comparable potency (IC50, 2.4 muM), as did several N-acyl-ethanolamides with cannabinoid receptor binding activity. Potassium current inhibition occurred through a pertussis toxin-insensitive mechanism and was not prevented by the cannabinoid receptor antagonist SR141716A. Utilizing excised patches of Kv1.2 channel-rich membrane as a rapid and sensitive bioassay, we found that phospholipase D stimulated the release of an endogenous anandamide-like K+ channel blocker from rat brain slices. Structure-activity studies were consistent with the possibility that the released blocker was either anandamide or another N-acyl-ethanolamide.
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PMID:Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels. 893 28

Morphine and anandamide stimulate the release of nitric oxide (NO) in diverse tissues. The present study examines the consequences of this action on neurotransmitter release in ganglia from two invertebrates: ventral chain ganglia from the leech Hirudo medicinalis and the pedal ganglion from the mussel Mytilus edulis. In these ganglia, preloaded serotonin (5-HT) and dopamine (DA) can be released by 50 mM KCl. Anandamide, an endogenous cannabinoid substance, suppresses the potassium-stimulated release of [3H]DA (80%), but not 5-HT, in a concentration-dependent manner, from the neural tissues of both. The effect of anandamide can be antagonized by pre-exposing the neural tissues of both animals to SR 141716A, a potent cannabinoid receptor antagonist. Prior treatment of the ganglia with N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, significantly diminishes the inhibitory effect of anandamide. Morphine also inhibits [3H]DA release in a naloxone- and L-NAME-sensitive manner. Anandamide and morphine act through separate mechanisms since the respective antagonists show no cross-reactivity. The NO donor, SNAP, depressed the potassium-stimulated release of preloaded [3H]DA, but not 5-HT, in the neural tissues of both animals. D-Ala2-Met5 enkephalinamide (DAMA) also inhibited the potassium-stimulated release of [3H]DA in a naloxone-sensitive process. However, the effect of DAMA was seen in the presence of L-NAME (10(-4) M), indicating that the opioid peptide inhibition of the presynaptic release of DA is not coupled to NO. We postulate that cannabinoids and their endogenous effectors play a prominent role in the regulation of catecholamine release in invertebrates via NO release as is the case for opiate alkaloids.
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PMID:Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. 927 29

We have found that phosphorylation of a G-protein-coupled receptor by protein kinase C (PKC) disrupts modulation of ion channels by the receptor. In AtT-20 cells transfected with rat cannabinoid receptor (CB1), the activation of an inwardly rectifying potassium current (Kir current) and depression of P/Q-type calcium channels by cannabinoids were prevented by stimulation of protein kinase C by 100 nM phorbol 12-myristate 13-acetate (PMA). In contrast, activation of Kir current by somatostatin was unaffected, and inhibition of calcium channels was only modestly attenuated. The possibility that PKC acted by phosphorylating CB1 receptors was confirmed by demonstrating that PKC phosphorylated a single serine (S317) of a fusion protein incorporating the third intracellular loop of CB1. Mutating this serine to alanine did not affect the ability of CB1 to modulate currents, but it eliminated disruption by PMA, demonstrating that PKC can disrupt ion channel modulation by receptor phosphorylation.
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PMID:Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor. 952


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