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)

Activation of cannabinoid receptors inhibits voltage-gated Ca2+ channels and activates K+ channels, reminiscent of other G-protein-coupled signaling pathways that produce presynaptic inhibition. We tested cannabinoid receptor agonists for effects on excitatory neurotransmission between cultured rat hippocampal neurons. Reducing the extracellular Mg2+ concentration to 0.1 mM elicited repetitive, transient increases in intracellular Ca2+ concentration ([Ca2+]i spikes) that resulted from bursts of action potentials, as measured by combined whole-cell current clamp and indo-1-based microfluorimetry. Pharmacological characterization indicated that the [Ca2+]i spikes required glutamatergic synaptic transmission. Cannabinoid receptor ligands inhibited stereoselectively the frequency of [Ca2+]i spiking in the rank order of potency: CP 54,939 > CP 55,940 > Win 55,212-2 > anandamide, with EC50 values of 0.36, 1.2, 2.7, and 71 nM, respectively. CP 55,940 was potent, but not efficacious, and reversed the inhibition produced by Win 55,212-2, indicating that it is a partial agonist. Inhibition of [Ca2+]i spiking by Win 55,212-2 was prevented by treatment of cultures with active, but not heat-treated, pertussis toxin. Win 55,212-2 (100 nM) inhibited stereoselectively CNQX-sensitive excitatory postsynaptic currents (EPSCs) elicited by presynaptic stimulation with an extracellular electrode, but did not affect the presynaptic action potential or currents elicited by direct application of kainate. Consistent with a presynaptic site of action, Win 55,212-2 increased both the number of response failures and the coefficient of variation of the evoked EPSCs. In contrast, cannabimimetics did not affect bicuculline-sensitive inhibitory postsynaptic currents. Thus, activation of cannabinoid receptors inhibits the presynaptic release of glutamate via an inhibitory G-protein.
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PMID:Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. 869 43

Cannabinoids have been shown to have anticonvulsant properties, but no studies have evaluated the effects of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy (AE) and status epilepticus (SE). This study investigated the anticonvulsant properties of the cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[1,2,3 de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone (WIN 55,212-2) in primary hippocampal neuronal culture models of both AE and SE. WIN 55,212-2 produced dose-dependent anticonvulsant effects against both spontaneous recurrent epileptiform discharges (SRED) (EC50 = 0.85 microM) and SE (EC50 = 1.51 microM), with total suppression of seizure activity at 3 microM and of SE activity at 5 microM. The anticonvulsant properties of WIN 55,212-2 in these preparations were both stereospecific and blocked by the cannabinoid type-1 (CB1) receptor antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A; 1 microM), showing a CB1 receptor-dependent pathway. The inhibitory effect of WIN 55,212-2 against low Mg2+-induced SE is the first observation in this model of total suppression of SE by a selective pharmacological agent. The clinically used anticonvulsants phenytoin and phenobarbital were not able to abolish low Mg2+-induced SE at concentrations up to 150 microM. The results from this study show CB1 receptor-mediated anticonvulsant effects of the cannabimimetic WIN 55,212-2 against both SRED and low Mg2+-induced SE in primary hippocampal neuronal cultures and show that these in vitro models of AE and SE may represent powerful tools to investigate the molecular mechanisms mediating the effects of cannabinoids on neuronal excitability.
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PMID:Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. 1646 64

Dendritic pruning and loss of synaptic contacts are early events in many neurodegenerative diseases. These effects are dynamic and seem to differ mechanistically from the cell death process. Cannabinoids modulate synaptic activity and afford protection in some neurotoxicity models. We investigated the effects of cannabinoids on activity-induced changes in the number of synapses between rat hippocampal neurons in culture. Morphology and synapses were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 (PSD95) fused to enhanced green fluorescent protein (GFP). Reducing the extracellular Mg2+ concentration to 0.1 mM for 4 h induced intense synaptic activity, which decreased the number of PSD95-GFP puncta by 45 +/- 13%. Synapse loss was an early event, required activation of N-methyl-D-aspartate receptors, and was mediated by the ubiquitin-proteasome pathway. The cannabinoid receptor full agonist WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)-methyl] pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl)-methanone monomethanesulfonate] (EC(50) = 2.5 +/- 0.5 nM) and the partial agonist Delta(9)-tetrahydrocannabinol (THC; EC(50) = 9 +/- 3 nM) inhibited PSD loss in a manner reversed by the CB1 receptor antagonist rimonabant [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide]. The protection was mimicked by inhibition of presynaptic Ca2+ channels, and WIN55,212-2 did not prevent PSD loss elicited by direct application of glutamate, suggesting a presynaptic mechanism. Prolonged exposure to WIN55,212-2, but not THC, desensitized the protective effect. Treating cells that had undergone PSD loss with WIN55,212-2 reversed the loss and enabled recovery of a full compliment of synapses. The modulation of synaptic number by acute and prolonged exposure to cannabinoids may account for some of the effects of these drugs on the plasticity, survival, and function of neural networks.
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PMID:Cannabinoids inhibit network-driven synapse loss between hippocampal neurons in culture. 1831 Apr 74