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

We tested the hypothesis that human CB1 cannabinoid receptors (hCB1) can sequester G(i/o)-proteins from a common pool and prevent other receptors from signaling. Human CB1 cannabinoid receptors were expressed in superior cervical ganglion (SCG) neurons by microinjection of hCB1 cDNA. Expression of hCB1 cannabinoid receptors abolished the Ca(2+) current inhibition by endogenous pertussis toxin-sensitive G(i/o)-coupled receptors for norepinephrine (NE) and somatostatin (SOM) but not by endogenous pertussis toxin-insensitive G(s)-coupled receptors for vasoactive intestinal polypeptide. Signaling by NE was rescued by expression of Galpha(oB), Gbeta(1), and Ggamma(3). Expression of mGluR2 metabotropic glutamate receptors, another pertussis toxin-sensitive G-protein-coupled receptor, had no effect on the signaling by NE or SOM. Some hCB1 receptors were constitutively active because the cannabinoid receptor inverse agonist SR 141617A enhanced the Ca(2+) current. Some hCB1 receptors also appear to be precoupled to G(i/o)-proteins because the cannabinoid agonist WIN 55,212-2 decreased the Ca(2+) current at a time when no G-proteins were available to couple to alpha(2)-adrenergic and somatostatin receptors. In SCG neurons microinjected with a lower concentration of hCB1 cDNA, the effect of SR 141716A was reduced, and the response to NE and SOM was partially restored. Subsequent to the application of SR 141716A, the Ca(2+) current inhibition by NE and SOM was abolished. These results suggest that both the active and inactive states of the hCB1 receptor can sequester G(i/o)-proteins from a common pool. Cannabinoid receptors thus have the potential to prevent other G(i/o)-coupled receptors from transducing their biological signals.
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PMID:The CB1 cannabinoid receptor can sequester G-proteins, making them unavailable to couple to other receptors. 1053 31

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase (ERK) that mediates CB1R- and mGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18-1. Mimicking constitutive phosphorylation of Munc18-1 results in a drastic decrease in synaptic transmission. ERK-mediated phosphorylation of Munc18-1 ultimately leads to degradation by the ubiquitin-proteasome system. Conversely, preventing ERK-dependent Munc18-1 phosphorylation increases synaptic strength. CB1R- and mGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation (DSE) are reduced upon ERK/MEK pathway inhibition and further reduced when ERK-dependent Munc18-1 phosphorylation is blocked. Thus, ERK-dependent Munc18-1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity.
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PMID:Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1. 2705 79