Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscarinic receptor stimulation increased the accumulation of 3H-inositol phosphates in PC12 cells whose phospholipids had been prelabeled with [3H]inositol. Muscarine also inhibited the increase in cyclic AMP (cAMP) accumulation caused by 5'-N-ethylcarboxamide adenosine or by vasoactive intestinal peptide. This effect of muscarine was apparently due to the inhibition of adenylate cyclase rather than to a stimulation of a cAMP specific phosphodiesterase. The muscarinic receptor antagonist pirenzepine inhibited both the stimulation of inositol-phospholipid metabolism and the inhibition of cAMP production with Ki values of 0.34 microM and 0.36 microM, respectively. PC12 cells contained a single class of N-[3H]methylscopolamine ([3H]NMS) binding sites. Competition studies with muscarine (KD, 15 microM) and pirenzepine (Ki, 0.12 microM) revealed no evidence for multiple muscarinic receptors. The Ki of pirenzepine for the inhibition of [3H]NMS binding and the inhibition of muscarinic actions is consistent with the possibility that this is not an M1 receptor. Muscarine inhibited cAMP accumulation in cells made deficient in protein kinase C; therefore, this protein kinase is probably not involved in mediating the inhibitory effect of muscarine. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate also inhibited cAMP accumulation in PC12 cells but the mechanism of this effect differed from that of muscarine. Bradykinin caused a large increase in the accumulation of 3H-inositol phosphates and [3H]diacylglycerol relative to muscarine but did not inhibit cAMP production. Oxotremorine inhibited cAMP accumulation but it did not stimulate inositol-phospholipid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic receptor stimulation increases inositol-phospholipid metabolism and inhibits cyclic AMP accumulation in PC12 cells. 254 58

Stimulation of muscarinic acetylcholine receptors (mAChR) elicits phosphatidylinositol turnover, which yields inositol phosphates (InsP) and diacylglycerol (DG) the latter activating protein kinase C (PKC). Activating PKC with phorbol esters inhibits mAChR agonist-stimulated phosphoinositide hydrolysis and InsP production. A possible mechanism of this inhibition may be down-regulation of mAChR by PKC. In the present work, rat cortical slices were preincubated with phorbol 12,13-dibutyrate (PDBu) followed by binding assays for [3H]quinuclidinyl benzilate [( 3H]QNB), [N-methyl-3H]scopolamine [( 3H]NMS) or [3H]pirenzepine [( 3H]PZ). Our data demonstrate that activation of PKC by phorbol esters causes a rapid down-regulation of muscarinic cholinergic receptors. This down-regulation is also rapidly reversible. Receptors on the cell surface appear to be more sensitive to the effect of PKC than do internal ones. This down-regulation occurs by a decrease in the number of receptors, rather than by changes in receptor affinity. The results suggest that PKC may exert negative feedback on its own activation by down-regulating the receptors that normally elicit phosphatidylinositol turnover.
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PMID:Phorbol 12,13-dibutyrate regulates muscarinic receptors in rat cerebral cortical slices by activating protein kinase C. 274 52

Following cholinergic denervation of the hippocampus by medial septal (MS) lesions, an unusual neuronal reorganization occurs in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus (hippocampal sympathetic ingrowth; HSI). Previously, we have found that with MS lesions, animals with (the HSI(+) group) and without (HSI(-) group) ingrowth differed in carbachol stimulated PI hydrolysis, in PKC activity, and in muscarinic cholinergic receptors (mAChR). In this study, performed in hippocampal slices obtained four weeks after MS lesions, we utilized the hydrophilic muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) and hydrophobic muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) in the presence of either 4-alpha-phorbol or phorbol 12,13-dibutyrate (PDBu) to determine the effect of MS lesions with and without ingrowth on PKC-mediated mAChR internalization. In the presence of PDBu, a group effect was observed in [3H]NMS binding, with control groups > HSI(+) group > HSI(-) group. However, [3H]QNB binding was similar across groups. These results suggest that the cholinergic denervation of the hippocampus enhances the internalization of mAChRs, which is modified in the presence of HSI.
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PMID:The effect of cholinergic denervation and hippocampal sympathetic ingrowth on the internalization of muscarinic receptors in rat hippocampus. 761 11

1 Oligodendrocytes, the myelin forming cells in the CNS, express muscarinic acetylcholine receptors (mAChR), primarily M3, coupled to various signal transduction pathways. 2 In the present study we have investigated whether mAChR undergo functional agonist-induced regulation in cultured oligodendrocyte progenitors and differentiated oligodendrocytes. 3 The muscarinic agonist, carbachol (CCh) caused a time-dependent desensitization of phosphoinositide (PI) hydrolysis, and the internalization and down-regulation of receptors. Short-time desensitization (5 min) of PI hydrolysis occurred without receptor internalization and reached 54% by 1 h. The same treatment decreased cell surface receptors labelled with the non-permeable ligand [(3)H]-NMS by 47%, while total receptor density ([(3)H]-scopolamine binding) decreased by 30%. Longer CCh treatment down-regulated receptors by 70% and desensitized the PI response by 80%. 4 Although protein kinase C (PKC) activation desensitized mAChR, CCh-mediated desensitization was independent of PKC. 5 Inhibition of receptor endocytosis by low temperature during the pre-stimulation period or in the presence of hyperosmotic sucrose (0.5 M) blocked desensitization, receptor internalization and down-regulation. 6 Recovery of surface mAChR and their functional activity following down-regulation was slow, returning to control levels by 24 h after agonist removal. In progenitor cells, dose-response curves for CCh-mediated PI hydrolysis and c-fos mRNA expression showed that newly synthesized mAChR were supersensitive after recovery. 7 Overall, the present results provide evidence of functional agonist-mediated mAChR regulation in brain oligodendroglial cells.
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PMID:Regulation of muscarinic receptor function in developing oligodendrocytes by agonist exposure. 1252 72

Signaling by muscarinic agonists is thought to result from the activation of cell surface acetylcholine receptors (mAChRs) that transmit extracellular signals to intracellular systems. In N1E-115 neuroblastoma cells, we detected both plasma membrane and intracellular M(1) -mAChRs using both biochemical and pharmacological methods. In intact cells, both plasma membrane and intracellular M(1) -mAChRs were detected by the hydrophobic ligand probe, 1-quinuclidinyl-[phenyl-4-(3) H]-benzilate ([(3) H]-QNB) whereas the hydrophilic probe, 1-[N-methyl-(3) H] scopolamine ([(3) H]-NMS), detected only cell surface receptors. These probes detected comparable numbers of receptors in isolated membrane preparations. Immunohistochemical studies with M(1) -mAChR antibody also detected both cell-surface and intracellular M(1) -mAChRs. Carbachol-stimulated phosphatidylinositol hydrolysis and Ca(2+) mobilization were completely inhibited by a cell-impermeable M(1) antagonist, muscarinic toxin -7 and the G(q/11) inhibitor YM-254890. However, carbachol-stimulated extracellular-regulated kinase 1/2 activation was unaffected by muscarinic toxin-7, but was blocked by the cell-permeable antagonist, pirenzepine. extracellular regulated kinase 1/2 phosphorylation was resistant to blockade of G(q/11) (YM-254890) and protein kinase C (bisindolylmaleimide I). Our data suggest that the geographically distinct M(1) -mAChRs (cell surface versus intracellular) can signal via unique signaling pathways that are differentially sensitive to cell-impermeable versus cell-permeable antagonists. Our data are of potential physiological relevance to signaling that affects both cognitive and neurodegenerative processes.
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PMID:Intracellular distribution of functional M(1) -muscarinic acetylcholine receptors in N1E-115 neuroblastoma cells. 2174 Apr 40