Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubating skeletal muscle fibers with forskolin, an activator of adenylate cyclase, increases the rate at which nicotinic acetylcholine receptors (AChRs) desensitize when exposed to ACh. Several reports indicate that this is due to the phosphorylation of AChRs by cAMP-dependent protein kinase, but other studies suggest that forskolin interacts with AChRs directly and that second-messenger systems are not required. To help clarify this issue, we studied the effects of forskolin and several other drugs on AChR function in embryonic rat myotubes. AChR function was studied by recording ACh-induced membrane depolarizations and ACh-induced single-channel currents. Our results indicate that forskolin at low concentrations enhances AChR desensitization through the action of a second messenger, most likely cAMP. An analog of forskolin that is much less effective in activating adenylate cyclase (1,9-dideoxyforskolin) is also much less potent in enhancing desensitization. Forskolin at low concentrations does not alter single-channel conductance or mean channel open time. However, when used at concentrations above 20 microM, forskolin may also exert direct drug effects on AChRs.
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PMID:Desensitization of acetylcholine receptors in rat myotubes is enhanced by agents that elevate intracellular cAMP. 245 25

The nicotinic acetylcholine receptor (AChR) is a substrate for at least three different protein kinases, and phosphorylation of the receptor has been shown to increase its rate of desensitization. However, the first messengers that regulate AChR phosphorylation have not yet been identified. This study demonstrates that calcitonin gene-related peptide (CGRP), a neuropeptide present in the axon terminals of the neuromuscular junction, regulates phosphorylation of the AChR in primary rat myotube cultures. CGRP, in the presence of the phosphodiesterase inhibitor Ro 20-1724, increased phosphorylation of the alpha and delta subunits of the AChR. CGRP-induced phosphorylation of the AChR had the same subunit specificity and temporal sequence as previously observed using forskolin or cAMP analogs. Phosphorylation of the AChR in the presence of CGRP appears to be mediated by CGRP-stimulated increases in cAMP levels leading to activation of cAMP-dependent protein kinase. The present results, taken together with the recent demonstration that CGRP increases the rate of AChR desensitization in mouse myotubes, suggest that CGRP may play a physiological role as a regulator of AChR desensitization by modulating AChR phosphorylation at the neuromuscular junction.
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PMID:Calcitonin gene-related peptide regulates phosphorylation of the nicotinic acetylcholine receptor in rat myotubes. 256 Jun 47

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

This article summarizes some of our knowledge concerning intracellular protein phosphorylation pathways in nerve cells. It also summarizes, very briefly, recent direct experimental evidence involving intracellular injection of protein kinases, protein kinase inhibitors, and substrates, indicating that protein phosphorylation mediates the actions of a variety of neurotransmitters on their target cells. Finally, it summarizes in somewhat greater detail the results of studies of three different types of substrate proteins that appear to regulate different types of biological responses in nerve cells: synapsin I, a substrate protein present in virtually all nerve terminals, which appears to regulate neurotransmitter release from those nerve terminals; the acetylcholine receptor, the phosphorylation of which regulates its rate of desensitization in the presence of acetylcholine; and DARPP-32, the phosphorylation of which converts it into a very potent phosphoprotein phosphatase inhibitor that may be involved in the regulation by the neuromodulator dopamine of the effects of the neurotransmitter glutamate. The identification and characterization of additional neuronal phosphoproteins can be expected to lead to the clarification of numerous additional molecular mechanisms by which signal transduction is carried out in nerve cells.
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PMID:Neuronal phosphoproteins. Mediators of signal transduction. 290 93

Previously, we found that the in vitro [32P]-autophosphorylation of the regulatory subunit of cyclic AMP-dependent protein kinase type II in rat soleus muscles is subject to a nerve-stump-length-dependent neuroregulation which indicates that this event is dependent upon some neural signal other than the impulse-directed release of acetylcholine. In this investigation, tetrodotoxin and alpha-bungarotoxin were also administered to further differentiate the effect of impulse-directed and spontaneously released acetylcholine upon this event and also upon the appearance of new acetylcholine receptors as measured by the binding of radioiodinated bungarotoxin. A 24 h blockade of cholinergic transmission with either neurotoxin did not change the phosphorylation level of the regulatory subunit, while a significant increase is observed when solei are surgically denervated for this period. The phosphorylation level and also the acetylcholine receptor content were increased only after more prolonged (48-96 h) muscle inactivity was produced with the neurotoxins. However, then their effects may not be solely related to alterations in cholinergic transmission. Taken together, our results do not support a trophic role for spontaneously released acetylcholine with respect to the two neurotrophic events studied.
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PMID:Role of cholinergic neuromuscular transmission in the neuroregulation of the autophosphorylatable regulatory subunit of cyclic AMP-dependent protein kinase type II and the acetylcholine receptor content in skeletal muscle. 303 65

Purified acetylcholine receptor is rapidly and specifically phosphorylated by partially purified protein kinase C, the Ca2+/phospholipid-dependent enzyme. The receptor delta subunit is the major target for phosphorylation and is phosphorylated on serine residues to a final stoichiometry of 0.4 mol of phosphate/mol of subunit. Phosphorylation is dose-dependent with a Km value of 0.2 microM. Proteolytic digestion of the delta subunit phosphorylated by either protein kinase C or the cAMP-dependent protein kinase yielded a similar pattern of phosphorylated fragments. The amino acids phosphorylated by either kinase co-localized within a 15-kDa proteolytic fragment of the delta subunit. This fragment was visualized by immunoblotting with antibodies against a synthetic peptide corresponding to residues 354-367 of the receptor delta subunit. This sequence, which contains 3 consecutive serine residues, was recently shown to include the cAMP-dependent protein kinase phosphorylation site (Souroujon, M. C., Neumann, D., Pizzighella, S., Fridkin, M., and Fuchs, S. (1986) EMBO J. 5, 543-546). Concomitantly, the synthetic peptide 354-367 was specifically phosphorylated in a Ca2+- and phospholipid-dependent manner by protein kinase C. Furthermore, antibodies directed against this peptide inhibited phosphorylation of the intact receptor by protein kinase C. We thus conclude that both the cAMP-dependent protein kinase and protein kinase C phosphorylation sites reside in very close proximity within the 3 adjacent serine residues at positions 360, 361, and 362 of the delta subunit of the acetylcholine receptor.
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PMID:Phosphorylation of the acetylcholine receptor by protein kinase C and identification of the phosphorylation site within the receptor delta subunit. 303 84

We have isolated a tyrosine-specific protein kinase from the acetylcholine receptor (AChR)-rich membranes of the electric ray Narke japonica. The enzyme is immunologically related to p60v-src, the product of the transforming gene of Rous sarcoma virus. A substantial phosphatidylinositol (PI) kinase activity was associated with this enzyme when it was purified through tyrosine-agarose affinity chromatography used previously for the purification of p60v-src. However, by subsequent chromatography on casein-agarose, most of the associated PI kinase activity was separated from the tyrosine kinase activity. The results suggest that the tyrosine-specific protein kinase in the AChR-rich membranes of N. japonica has no intrinsic PI kinase activity.
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PMID:A p60v-src-related tyrosine kinase in the acetylcholine receptor-rich membranes of Narke japonica: association and dissociation of phosphatidylinositol kinase activity. 309 16

The acetylcholine receptor (AChR) content and the autophosphorylation of the regulatory subunit of cyclic AMP-dependent protein kinase type II (R-II) were evaluated in rats soleus muscles at 24, 30 and 66 hr after surgical denervation by cutting the nerve at a short distance (short-nerve-stump) and at a long distance (long-nerve-stump) from the muscle. AChR content was based on the specific binding of [125I]alpha-bungarotoxin (BUTX); changes in the autophosphorylation of R-II were based upon the predominant in vitro 32P-phosphorylation of a 56-Kd soluble protein in cytosolic fractions of solei. The AChR content and the 32P-autophosphorylation of R-II were increased in samples from short-nerve-stump solei, but not from long-nerve-stump solei, after a denervation-time of 30 hr. This nerve-stump-length dependency indicates that the two denervation effects are not related to the immediate halt of impulse-evoked muscle contractility. Furthermore, the results show that alterations in the 32P-autophosphorylation of R-II occurred before, as well as whenever, increases in the AChR content were found. Speculatively, this temporal relationship may be significant with respect to the potential role of R-II in gene expression.
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PMID:Temporal relationship between nerve-stump-length-dependent changes in the autophosphorylation of a cyclic AMP-dependent protein kinase and the acetylcholine receptor content in skeletal muscle. 323 7

We have investigated the mechanisms regulating the clustering of nicotinic acetylcholine receptor (AChR) on the surface of cultured embryonic chick muscle cells. Treatment of these cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C, was found to cause a rapid dispersal of AChR clusters, as monitored by fluorescence microscopy of cells labeled with tetramethylrhodamine-conjugated alpha-bungarotoxin. The loss of AChR clusters was not accompanied by an appreciable change in the amount of AChR on the surface of these cells, as measured by the specific binding of [125I]Bgt. Analysis of the phosphorylation pattern of immunoprecipitable AChR subunits showed that the gamma- and delta-subunits are phosphorylated by endogenous protein kinase activity in the intact muscle cells, and that the delta-subunit displays increased phosphorylation in response to TPA. Structural analogues of TPA which do not stimulate protein kinase C have no effect on AChR surface topography or phosphorylation. Exposure of chick myotubes to the cholinergic agonist carbamylcholine was found to cause a dispersal of AChR clusters with a time course similar to that of TPA. Like TPA, carbamylcholine enhances the phosphorylation of the delta-subunit of AChR. The carbamylcholine-induced redistribution and phosphorylation of AChR is blocked by the nicotinic AChR antagonist d-tubocurarine. TPA and carbamylcholine have no effect on cell morphology during the time-course of these experiments. These findings indicate that cell surface topography of AChR may be regulated by phosphorylation of its subunits and suggest a mechanism for dispersal of AChR clusters by agonist activation.
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PMID:Induction of phosphorylation and cell surface redistribution of acetylcholine receptors by phorbol ester and carbamylcholine in cultured chick muscle cells. 341 78

Acetylcholine receptor-enriched membranes from the electric organ of Torpedo californica show a major band at Mr 43,000 on NaDodSO4/polyacrylamide gels. This band is composed of three polypeptides: nu 1, nu 2, and nu 3. Polypeptide nu 1 has been found to be localized exclusively at the innervated face of the electrocyte and at the neuromuscular junction in rat muscle. We show here that monoclonal antibody to nu 1 precipitates a radioactive Mr 43,000 polypeptide from detergent-solubilized extracts of Torpedo membranes covalently labeled with periodate-oxidized [alpha-32P]ATP. The monoclonal antibody also precipitates protein kinase activity from neutralized pH 11 extracts of the acetylcholine receptor-rich membranes. These data suggest that nu 1 is a postsynaptic membrane protein kinase.
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PMID:nu 1, a Mr 43,000 component of postsynaptic membranes, is a protein kinase. 345 69


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