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)

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 present work was undertaken to study the metabolic response of C6 glioma cells to physiologically relevant doses of delta9-tetrahydrocannabinol (THC), the major active component of marijuana. At those concentrations (i.e. nanomolar range), THC produced a dose-dependent increase in the rates of glucose oxidation to CO2 and glucose incorporation into phospholipids and glycogen. The THC-induced stimulation of glucose utilization was (i) dose-dependent up to 100 nM THC, (ii) mimicked by the synthetic cannabinoid HU-210, and (iii) prevented by pertussis toxin and the CB1 receptor antagonist SR141716A. In contrast to THC, forskolin markedly depressed CO2 production, phospholipid synthesis and glycogen synthesis from glucose. The forskolin-induced inhibition of glucose utilization was (i) mimicked by dibutyryl-cAMP, and (ii) prevented by THC, HU-210 and H-7, an inhibitor of the cAMP-dependent protein kinase. Likewise, THC was able to antagonize in part the forskolin-induced elevation of intracellular cAMP concentration, and this antagonistic effect was prevented by SR141716A. However, THC per se did not affect basal cAMP concentration. Results thus indicate that physiologically relevant doses of THC stimulate glucose metabolism in C6 glioma cells through a cannabinoid receptor-mediated process. Although cannabinoid receptors may be coupled to inhibition of adenylyl cyclase in C6 glioma cells, this does not seem to be the mechanism involved in the THC-induced stimulation of glucose metabolism.
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PMID:Delta9-tetrahydrocannabinol stimulates glucose utilization in C6 glioma cells. 936 16

It has been suggested that the cannabinoid receptor type 1 (CB1), a G protein-coupled receptor, is internalized after agonist binding and activation of the second messenger pathways. It is proposed that phosphorylation enhances the down-regulation of the CB1 receptor, thus contributing to tolerance. Alterations in phosphorylation of proteins in the signal transduction cascade after CB1receptor activation could also alter tolerance to cannabinoids. We addressed our hypothesis by evaluating the role of several kinases in antinociceptive tolerance to Delta(9)-tetrahydrocannabinol (THC). We evaluated cAMP-dependent protein kinase (PKA) using KT5720, a PKA inhibitor; protein kinase C (PKC) using bisindolylmaleimide I, HCl (bis), a PKC inhibitor; cGMP-dependent protein kinase (PKG) using KT5823, a PKG inhibitor; beta-adrenergic receptor kinase (beta-ARK) using low molecular weight heparin (LMWH), a beta-ARK inhibitor; and phosphatidylinositol-3 kinase (PI3-K) using 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a PI3-K inhibitor and PP1, a Src family tyrosine kinase inhibitor. The cAMP analog used was dibutyryl-cAMP and the cGMP analog used was dibutyryl-cGMP. Our data indicate that selective kinases may be involved in cannabinoid tolerance. Mice and rats were rendered tolerant to Delta(9)-THC. The PKG inhibitor KT5823, the beta-ARK inhibitor LMWH, the PI3-K inhibitor LY294002, and inhibition of PKC by bis had no effect on tolerance. At a higher dose, bis attenuated the antinociceptive effect of delta(9)-THC in nontolerant mice. PP1, the Src family tyrosine kinase inhibitor, and KT5720, the PKA inhibitor, reversed THC-induced tolerance. In addition, inhibition of PKA reversed a decrease in dynorphin release shown to accompany THC tolerance in rats. These data support a role for PKA and Src tyrosine kinase in phosphorylation events in delta(9)-THC-tolerant mice.
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PMID:The role of several kinases in mice tolerant to delta 9-tetrahydrocannabinol. 1260 57

The endocannabinoid system regulates food intake, energy, and glucose metabolism at both central and peripheral levels. We have investigated the mechanism by which it may control glucose uptake in skeletal muscle cells. Detectable levels of the cannabinoid receptor type 1 (CB1) were revealed in L6 cells. Exposure of differentiated L6 myotubes to the CB1 antagonist rimonabant (SR141716) selectively increased 2-deoxyglucose uptake (2-DG) in a time- and dose-dependent manner. A similar effect was induced by genetic silencing of CB1 by small interfering RNA. Protein expression profiling revealed that both the regulatory p85 and the catalytic p110 subunits of the phosphatidylinositol-3-kinase (PI3K) were increased by SR141716. No significant change in the cellular content of other known molecules regulating PI3K was observed. However, phosphoinositide-dependent kinase-1, Akt/protein kinase B, and protein kinase Czeta activities were rapidly induced after SR141716 treatment of L6 cells in a PI3K-dependent manner. The stimulatory effect of SR141716 on PI3K expression and activity was largely prevented by N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H-89), an inhibitor of the cAMP-dependent protein kinase. Moreover, SR141716-stimulated 2-DG uptake was blunted by the coincubation either with H-89 or with the PI3K inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), both in L6 cells and in mouse primary myocytes. Thus, modulation of CB1 regulates glucose uptake at the level of the PI3K signaling system in skeletal muscle cells. Interfering with CB1 signaling may therefore ameliorate glucoregulatory functions in peripheral tissues.
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PMID:The cannabinoid CB1 receptor antagonist rimonabant stimulates 2-deoxyglucose uptake in skeletal muscle cells by regulating the expression of phosphatidylinositol-3-kinase. 1880 18

Excessive inflammatory responses are involved in secondary brain injury during germinal matrix hemorrhage (GMH). The process of microglial polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes is considered to occur in a major immunomodulatory manner during brain inflammation. We previously found that cannabinoid receptor-2 (CB2R) stimulation attenuated microglial accumulation and brain injury following experimental GMH. However, whether CB2R has effects on microglial polarization after GMH remains unclear. Herein, we investigated the effects of CB2R stimulation on neuroinflammation after experimental GMH and the potential mechanisms that mediate M1/M2 microglial phenotype regulation. The results indicated that during the GMH acute phase, microglia primarily polarized to the M1 phenotype and induced an overwhelming release of pro-inflammatory cytokines. However, JWH133, a selective CB2R agonist, significantly prevented the pro-inflammatory cytokine release while promoting an M1 to M2 phenotype transformation in microglia, resulting in an increased anti-inflammatory cytokine release. Moreover, in thrombin-induced rat primary microglial cells, JWH133 reduced the pro-inflammatory cytokine levels and M1 phenotype by enhancing the acquisition of the M2 phenotype. Additionally, JWH133 facilitated synthesis of cyclic AMP (cAMP) and its downstream effectors, phosphorylated cAMP-dependent protein kinase (p-PKA) and exchange protein activated by cyclic-AMP 1 (Epac1). The promoting effects of JWH133 on M2 polarization were attenuated with a specific PKA inhibitor but not with an Epac inhibitor, indicating that the cAMP/PKA signaling pathway was involved in the JWH133 effects. This is the first study to propose that promotion of microglial M2 polarization through the cAMP/PKA pathway participates in the CB2R-mediated anti-inflammatory effects after GMH induction. The results will help to further understand the mechanisms that underlie neuroprotection by CB2R in GMH and promote clinical translational research for CB2R agonists.
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PMID:Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model. 2726 Oct 88

The cannabinoid receptor-2 (CB2R) was initially thought to be the "peripheral cannabinoid receptor." Recent studies, however, have documented CB2R expression in the brain in both glial and neuronal cells, and increasing evidence suggests an important role for CB2R in the central nervous system inflammatory response. Intracerebral hemorrhage (ICH), which occurs when a diseased cerebral vessel ruptures, accounts for 10-15% of all strokes. Although surgical techniques have significantly advanced in the past two decades, ICH continues to have a high mortality rate. The aim of this study was to investigate the therapeutic effects of CB2R stimulation in acute phase after experimental ICH in rats and its related mechanisms. Data showed that stimulation of CB2R using a selective agonist, JWH133, ameliorated brain edema, brain damage, and neuron death and improved neurobehavioral outcomes in acute phase after ICH. The neuroprotective effects were prevented by SR144528, a selective CB2R inhibitor. Additionally, JWH133 suppressed neuroinflammation and upregulated the expression of microglial M2-associated marker in both gene and protein level. Furthermore, the expression of phosphorylated cAMP-dependent protein kinase (pPKA) and its downstream effector, cAMP-response element binding protein (CREB), were facilitated. Knockdown of CREB significantly inversed the increase of M2 polarization in microglia, indicating that the JWH133-mediated anti-inflammatory effects are closely associated with PKA/CREB signaling pathway. These findings demonstrated that CB2R stimulation significantly protected the brain damage and suppressed neuroinflammation by promoting the acquisition of microglial M2 phenotype in acute stage after ICH. Taken together, this study provided mechanism insight into neuroprotective effects by CB2R stimulation after ICH.
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PMID:Inflammatory Regulation by Driving Microglial M2 Polarization: Neuroprotective Effects of Cannabinoid Receptor-2 Activation in Intracerebral Hemorrhage. 2826 Nov 99