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

The signaling pathway connecting membrane depolarization and gene activity in skeletal muscle remains largely unknown. Using transcription elongation (run-on) analysis we have found that electrical stimulation of denervated chick skeletal muscle in vivo rapidly and selectively results in inactivation of acetylcholine receptor (AChR) subunit genes. We have studied the possible involvement of protein kinase C (PKC) in this response and have observed that electrical stimulation increases the activity of PKC in the nucleus by over two orders of magnitude within 10 min; phorbol esters, within minutes after intramuscular application, block AChR subunit genes in the absence of electrical activity; and the activity-triggered gene inactivation is blocked by the protein kinase inhibitor staurosporine or by enzyme depletion resulting from chronic pretreatment of muscle with phorbol esters. We conclude that PKC is an integral component of the pathway coupling membrane excitation and AChR gene control.
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PMID:Protein kinase C couples membrane excitation to acetylcholine receptor gene inactivation in chick skeletal muscle. 138 82

The delta-subunit of the nicotinic acetylcholine receptor from Torpedo californica electric tissue isolated form receptor purified in the absence of protein phosphatase inhibitors contains a total of four phosphate groups. Three of these are shown to represent phosphoserine groups. The fourth possible represents phosphotyrosine. The phosphate groups are localized within the primary structure: We found phosphoserine in positions delta S361 and delta S377, the predicted sites phosphorylated by PKA and PKC, respectively. In addition, we found that position delta S362 is also phosphorylated. Phosphorylation experiments with the synthetic peptide delta L357-delta K368 show that phosphorylation of this novel site can be catalyzed by PKA and by PKC. It is concluded that the delat-subunit of the acetylcholine receptor is stably and not transiently phosphorylated. Implications for the physiological functions of receptor phosphorylation are discussed.
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PMID:Phosphorylation sites of the nicotinic acetylcholine receptor. A novel site detected in position delta S362. 170 13

Both 4-beta-12,13-dibutyrate phorbol-ester (PDBu) (EC50% = 82 +/- 12 nM) and carbachol (EC50% = 2.3 +/- 0.3.5 microM) enhanced dopamine (DA) release from rabbit striatal slices. No additivity was observed when slices were treated simultaneously with 0.1 microM PDBu and 10 microM carbachol. Pretreatment with PDBu (0.01-0.1 microM) abolished carbachol-induced facilitation of DA release. Pretreatment with carbachol (3-100 microM) antagonized the enhancement in DA release produced by PDBu. The effect of carbachol was blocked by atropine (0.1 microM) and not by hexamethonium (10 microM). The effect of PDBu was not modified by the acetylcholine receptor (AChR) antagonists. If muscarinic (MAChR) MAChR were blocked by atropine (0.1 microM), pretreatment with carbachol failed to antagonize PDBu-induced facilitation of DA release. This is the first report to indicate that activation of M1-MAChR by an agonist prevents the effects of an active phorbol-ester. We suggest that activation of M1-MAChR enhances DA release possibly through activation of PKC.
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PMID:Carbachol-phorbol ester interactions at muscarinic receptors modulating dopamine release from rabbit striatal slices. 176 98

Protein kinase C has previously been implicated in the regulation of chicken acetylcholine receptor (AChR) gene expression. To investigate the molecular basis of this regulation, the promoter of the AChR alpha-subunit (alpha AChR) gene was linked to a reporter gene and introduced into cultured chick myotubes by transient transfection. Treatment of myotubes with protein-kinase-C-activating phorbol esters was found to inhibit promoter activity. These inhibitory actions were mediated by promoter sequences between nucleotides -110 and -45, relative to the start point of transcription of the alpha AChR gene. In particular, phorbol-ester responsiveness could be conferred by a short DNA sequence that contains one of the two MyoD binding sites of the alpha AChR gene muscle-specific enhancer. 12-O-Tetradecanoylphorbol 13-acetate was found to inhibit rapidly and potently the expression of mRNAs coding for the myogenic regulators CMD1 and myogenin. Moreover, its inhibitory effect on the alpha AChR gene promoter could be attenuated by cotransfection of a MyoD1 expression vector. These results provide a molecular basis for the previously demonstrated involvement of protein kinase C in the regulation of alpha AChR biosynthesis. In addition, they lend further support to the notion that myogenic proteins play an important role in the control of alpha AChR gene expression.
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PMID:Phorbol esters inhibit the activity of the chicken acetylcholine receptor alpha-subunit gene promoter. Role of myogenic regulators. 176 95

In the adult motor endplate the acetylcholine receptor protein (AChR) is strictly localized under the motor nerve ending, whereas in the noninnervated myotube it is distributed all over the surface of the cell. The genesis of this anisotropic distribution involves a differential regulation of AChR gene transcription. In situ hybridization with AChR subunit probes discloses high levels of unspliced and mature mRNA all over differentiating myotubes. After the entry of the exploratory motor axons, the mRNA clusters located outside the endplate decrease in number and become restricted to the subneural "fundamental" nuclei. Denervation causes a reappearance of unspliced and mature mRNA in extrajunctional areas. A compartmentalized expression of AChR genes take place during endplate formation. Chronic paralysis of the embryo interferes with the disappearance of extrajunctional AChR that, thus, represents an electrical activity-dependent repression of AChR genes. The entry of Ca2+ ions through the sarcolemmal membrane during electrical activity and the activation of protein kinase C plausibly contribute to this membrane-to-gene regulation. The maintenance and late increase in AChR number at the endplate requires the intervention of an anterograde signal or signals, of neural origin. Several factors have been suggested to play a role in this process, such as an acetylcholine receptor-inducing activity (ARIA), ascorbic acid, or calcitonin gene-related peptide (CGRP), a peptide known to coexist with acetylcholine in spinal cord motoneurons. In cultured chick muscle cells, CGRP increases the concentration of surface AChR and alpha-subunit unspliced and mature mRNA and stimulates membrane-bound adenylate cyclase, suggesting that distinct second messengers are involved in the regulation of AChR biosynthesis by electrical activity and by CGRP. The data are interpreted in terms of a model in which it is assumed that (i) in the adult muscle fiber, different stages of gene expression occur in the nuclei in subneural and extrajunctional areas, and (ii) different second messengers elicited by neural factors or electrical activity regulate the state of transcription of these nuclei via trans-acting allosteric proteins binding to cis-acting DNA regulatory elements. The upstream flanking regions of several of the AChR subunit genes reveal ubiquitous DNA elements such as TATA and CAAT boxes, Sp1 binding sites and SV40 core enhancer sites, and muscle-specific MyoD (CANNTG) elements. The contribution of some of these elements to the differential regulation of the multiple AChR subunits is discussed.
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PMID:Compartmentalized transcription of acetylcholine receptor genes during motor endplate epigenesis. 188 10

Recent studies have provided evidence for a role of protein phosphorylation in the regulation of the function of various potassium and calcium channels (for reviews, see refs 1, 2). As these ion channels have not yet been isolated and characterized, it has not been possible to determine whether phosphorylation of the ion channels themselves alters their properties or whether some indirect mechanism is involved. In contrast, the nicotinic acetylcholine receptor, a neurotransmitter-dependent ion channel, has been extensively characterized biochemically and has been shown to be directly phosphorylated. The phosphorylation of this receptor is catalysed by at least three different protein kinases (cyclic AMP-dependent protein kinase, protein kinase C and a tyrosine-specific protein kinase) on seven different phosphorylation sites. However, the functional significance of phosphorylation of the receptor has been unclear. We have now examined the functional effects of phosphorylation of the nicotinic acetylcholine receptor by cAMP-dependent protein kinase. We investigated the ion transport properties of the purified and reconstituted acetylcholine receptor before and after phosphorylation. We report here that phosphorylation of the nicotinic acetylcholine receptor on the gamma- and delta-subunits by cAMP-dependent protein kinase increases the rate of the rapid desensitization of the receptor, a process by which the receptor is inactivated in the presence of acetylcholine (ACh). These results provide the first direct evidence that phosphorylation of an ion channel protein modulates its function and suggest that phosphorylation of postsynaptic receptors in general may play an important role in synaptic plasticity.
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PMID:Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization. 242 85

Using primary cultures of chicken myotubes, we investigated the involvement of protein kinase C and Ca2+ in the repression of nicotinic acetylcholine receptor (AChR) biosynthesis by electrical activity. Treatment with the Ca2+ channel blocker verapamil or the Na+ channel blocker tetrodotoxin increased alpha subunit mRNA levels 11.5- to 15-fold. The effect of tetrodotoxin was abolished in the presence of the Ca2+ ionophore A23187. Dantrolene, which blocks Ca2+ efflux from the sarcoplasmic reticulum, caused only a 1.7-fold increase in alpha subunit mRNA levels. Down regulation of protein kinase C by prolonged exposure to the phorbol ester TPA or inhibition of protein kinase C by staurosporine led to 8- to 10-fold increases in alpha subunit mRNA levels. Mature and precursor forms of AChR alpha subunit mRNA were found to vary in parallel throughout all of these treatments, suggesting that protein kinase C and Ca2+ ions may modulate AChR alpha subunit biosynthesis at the transcriptional level.
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PMID:Regulation of muscle AChR alpha subunit gene expression by electrical activity: involvement of protein kinase C and Ca2+. 251 49

The Calcitonin-Gene Related Peptide (CGRP), a neuropeptide present in chick spinal cord motoneurons, increases the levels of surface acetylcholine receptor (AChR) and of the AChR alpha-subunit mRNA in cultured chick myotubes. Cholera toxin (CT), an activator of adenylate cyclase, produces a similar effect which does not add up with that of CGRP. Consistent with this observation, CGRP increases the content of cyclic AMP in chick muscle cells in culture. Tetrodotoxin (TTX), a blocker of voltage-sensitive Na+ channels, elevates the levels of AChR and of AChR alpha-subunit mRNA. This effect is additive with that of CGRP or CT. TPA (12-O-tetradecanoyl phorbol-13-acetate), an activator of protein kinase C, decreases the level of AChR but has no effect on the level of AChR alpha-subunit mRNA. Interestingly, TPA inhibits the increase of AChR alpha-subunit mRNA caused by TTX without affecting that produced by CGRP or CT. These data suggest that CGRP, which coexists with acetylcholine in spinal cord motoneurons, could be one of the anterograde factors (or a model of such factor) responsible for the enhanced expression of the genes coding for AChR subunits in subneural nuclei, via the activation of adenylate cyclase. Muscle electrical activity would then inhibit the expression of the same genes in extrajunctional nuclei, via another intracellular pathway.
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PMID:[Possible trophic role on the neuromuscular junction of a neuropeptide co-existing with acetylcholine in motor neurons of the spinal cord]. 254 40

Studies in the past several years have provided direct evidence that protein phosphorylation is involved in the regulation of neuronal function. Electrophysiological experiments have demonstrated that three distinct classes of protein kinases, i.e., cyclic AMP-dependent protein kinase, protein kinase C, and CaM kinase II, modulate physiological processes in neurons. Cyclic AMP-dependent protein kinase and kinase C have been shown to modify potassium and calcium channels, and CaM kinase II has been shown to enhance neurotransmitter release. A large number of substrates for these protein kinases have been found in neurons. In some cases (e.g., tyrosine hydroxylase, acetylcholine receptor, sodium channel) these proteins have a known function, whereas most of these proteins (e.g., synapsin I) had no known function when they were first identified as phosphoproteins. In the case of synapsin I, evidence now suggests that it regulates neurotransmitter release. These studies of synapsin I suggest that the characterization of previously unknown neuronal phosphoproteins will lead to the elucidation of previously unknown regulatory processes in neurons.
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PMID:Protein phosphorylation and neuronal function. 258 86

Spinal cord cells co-cultured with primary chick myotubes caused a 1.5-3-fold increase in the number of muscle surface acetylcholine receptors assayed with [125I]alpha-bungarotoxin. This increase did not result from the metabolic stabilization of the acetylcholine receptor protein and was at least partially due to a stimulation of acetylcholine receptor biosynthesis up to the level of the accumulation of alpha-subunit mature and partially spliced precursor mRNAs. A medium conditioned by spinal cord cells also caused a rise in acetylcholine receptor number. This increase did not coincide with an augmentation of the intracellular cyclic AMP level as reported for the neuropeptide calcitonin gene-related peptide. In contrast, spinal cord cells and the medium conditioned by them potentiated the effect of calcitonin gene-related peptide on acetylcholine receptor number. Stimulation of acetylcholine receptor synthesis by the conditioned medium was blocked by the protein kinase C activator 12-O-tetradecanoyl phorbol-13-acetate and by the calcium ionophore A23187. These two compounds have already been reported to block the increase of acetylcholine receptor number produced by the voltage sensitive sodium channel antagonist tetrodotoxin which stimulates acetylcholine receptor biosynthesis by blocking spontaneous electrical activity of the cultured muscle cells. The possibility that different neural factors and second messenger systems are involved in the regulation of acetylcholine receptor biosynthesis during the development of the neuromuscular junction is discussed.
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PMID:Acetylcholine receptor expression in primary cultures of embryonic chick myotubes--II. Comparison between the effects of spinal cord cells and calcitonin gene-related peptide. 258 56


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