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)

A monoclonal antibody designated as MAC-L1 immunoprecipitated [3H]PN200-110-labeled calcium channels of chick cardiac and skeletal muscle. On specific immunoprecipitation of 125I-labeled proteins, two large polypeptides (Mr 197,000 and 139,000 for heart, and 172,000 and 135,000 for skeletal muscle, under reducing conditions) were identified as the major components of these channels. Both polypeptides were found to exist together as a complex in 1% digitonin, but to become separated from each other in 1% Triton X-100. The 197 and 172 kDa peptides of cardiac and skeletal muscles, respectively, were photolabeled with [3H]azidopine. Under nonreducing conditions, the 139 kDa polypeptide of heart and the 135 kDa polypeptide of skeletal muscle took on larger molecular weights of 192,000 and 190,000, respectively. The 139 kDa but not the 197 kDa component of the heart was capable of binding to wheat germ agglutinin-Sepharose. Among the polypeptides specifically precipitated by MAC-L1, a 165 kDa peptide of skeletal muscle was phosphorylated by cAMP-dependent protein kinase. In contrast, a minor 99 kDa polypeptide, but not the major 197 kDa polypeptide, of the heart was phosphorylated by this kinase. These results suggest that the dihydropyridine-sensitive cardiac calcium channel has alpha 1 and alpha 2 subunits that are homologous but not identical to those of the skeletal muscle calcium channel.
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PMID:Molecular characterization of 1,4-dihydropyridine-sensitive calcium channels of chick heart and skeletal muscle. 216 21

Isolated perfused rabbit ear arteries contract when treated with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of the calcium-activated, phospholipid-dependent protein kinase or C-kinase. Under conditions where the calcium concentration in the perfusate is 1.5 mM and the potassium concentration is 4.8 mM, there is a latent period of 70 +/- 19 min (mean +/- S.E.M., n = 10) between TPA addition and the onset of the contractile response. Once initiated, the contractile response is progressive and sustained. When perfusion conditions are altered in such a way as to modify calcium flux across the plasma membrane (i.e., raising the extracellular calcium concentration to 2.5 mM Ca++, raising the extracellular potassium concentration to 10 mM, and/or preincubating the tissues in media containing 100 nM Bay K 8644, a potent calcium channel agonist), the latency period between TPA addition and initiation of the contractile response is significantly reduced (2.5 mM Ca++, 37 +/- 7 min; 10 mM K+ and 2.5 mM Ca++, 11 +/- 3 min; 100 nM Bay K 8644 and 1.5 mM Ca++, 20 +/- 7 min; 100 nM Bay K 8644 and 2.5 mM Ca2+, 8.5 +/- 1.7 min; 10 mM K+ and 100 nM Bay K 8644, 11 +/- 5 min). Likewise, the combination of 2.5 mM calcium, 100 nM Bay K 8644, and 3.3 microM ouabain results in a contractile response 4.5 +/- 2.0 min after TPA addition (means +/- S.E.M., n = 4). Control tissues (absence of TPA addition) run simultaneously show no contractile responses to the various Ca++ flux regulators even after 90 min of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma membrane calcium flux, protein kinase C activation and smooth muscle contraction. 241 29

Corticotropin (ACTH)-releasing factor, vasoactive intestinal peptide, and catecholamines--hormones that stimulate ACTH secretion and cAMP generation--increased cytosolic calcium in AtT-20 cells. The increase in intracellular calcium is presumably a consequence of the stimulated cAMP synthesis, since forskolin, an activator of the catalytic unit of adenylate cyclase, and the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8Br-cAMP) also increased the cytosolic levels of this ion. Pretreatment with somatostatin, a neuropeptide that inhibits stimulation of the adenylate cyclase system and the secretion of ACTH blocked the increase of cytosolic calcium. The effect of 8Br-cAMP, which bypasses the cyclase, was not inhibited by somatostatin pretreatment. The source of the increased calcium appears to be mainly extracellular. This is indicated by the inability of the secretagogues to increase cytosolic calcium in a medium deprived of this ion or in the presence of blockers of voltage-gated calcium channels. The involvement of calcium channels in the calcium rise evoked by the secretagogues was supported by experiments using the whole-cell patch-clamp technique. In these experiments 8Br-cAMP increased voltage-dependent calcium currents. These results suggest the following chain of events in the receptor-mediated elevation of cytosolic calcium and the concomitant release of ACTH from AtT-20 cells: hormone-receptor binding----cAMP synthesis----protein kinase activation----calcium channel activation----increase in cytosolic calcium----many steps----ACTH release. Phorbol myristate acetate, a compound which does not stimulate cAMP generation but enhances the release of ACTH in AtT-20 cells, decreased the cytosolic calcium level.
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PMID:Hormone secretagogues increase cytosolic calcium by increasing cAMP in corticotropin-secreting cells. 241 78

The modulation of voltage-activated calcium currents by protein kinases provides excitable cells with a mechanism for regulating their electrical behaviour. At the single channel level, modulation of calcium current has, to date, been characterized only in cardiac muscle, where beta-adrenergic agonists, acting through cyclic AMP-dependent protein kinase, enhance the calcium current by increasing channel availability and opening. We now report that enhancement of calcium current in the peptidergic bag cell neurons of Aplysia by protein kinase C occurs through a different mechanism, the recruitment of a previously covert class of calcium channel. Under control conditions, bag cell neurons contain only one class of voltage-activated calcium channel with a conductance of approximately 12 pS. After exposure to agents that activate protein kinase C, these neurons also express a second class of calcium channel with a different unitary conductance (approximately 24 pS) that is never seen in untreated cells.
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PMID:Stimulation of protein kinase C recruits covert calcium channels in Aplysia bag cell neurons. 243 53

Two classes of calcium channels were activated by membrane depolarization in cell-free membrane patches from GH3 cells, an electrically excitable cell line derived from a mammalian pituitary tumor. One class had a conductance of approximately 10 pS in 90 mM barium, had a threshold of activation near -40 mV, and was inactivated rapidly at holding potentials more positive than -80 mV. The other class, with a conductance of approximately 23 pS and a threshold nearer -20 mV, did not inactivate in barium but stopped responding to depolarization altogether when the cytoplasmic side of the patch was exposed to a standard physiological saline solution. Buffering the concentration of calcium ions to less than 10 nM on the cytoplasmic side did not prevent this loss of activity. However, activity was restored and maintained for the duration of the patch when the catalytic subunit of cAMP-dependent protein kinase was added with MgATP to the cytoplasmic side of the membrane. Cell-free patch formation in the presence of the dihydropyridine, BAY K 8644, also delayed the loss of activity, but unlike the catalytic subunit plus ATP, BAY K 8644 alone did not restore activity when it was added after the channels no longer responded to depolarization. Evidently the dihydropyridine-sensitive class of voltage-activated calcium channels must be phosphorylated in order to open when the membrane is depolarized. That hypothesis provides a simple framework for understanding the modulation of calcium channel gating by neurotransmitters, calcium ions, and dihydropyridines.
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PMID:Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarization. 243 33

Partially purified fractions of dihydropyridine and phenylalkylamine receptors associated with voltage-dependent calcium channels in rabbit skeletal muscle were found to contain two glycopeptides of similar molecular weight. A peptide of approximately 165 kDa was photoaffinity labelled with an arylazido-phenylalkylamine Ca channel inhibitor and also was phosphorylated with cAMP-dependent protein kinase. Another peptide of 170 kDa could be distinguished from the 165 kDa peptide by peptide mapping and differences in electrophoretic mobility. The results suggest that the 165 kDa peptide contains the sites responsible for regulation of calcium channel activity by calcium channel inhibitors as well as by neurotransmitters that regulate its activity in a cAMP-dependent manner.
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PMID:Photoaffinity labelling and phosphorylation of a 165 kilodalton peptide associated with dihydropyridine and phenylalkylamine-sensitive calcium channels. 244 23

Activation of the cardiac beta-adrenergic receptor stimulates cAMP levels and activates cAMP-dependent protein kinase. The kinase phosphorylates the calcium channel and enhances thereby the availability and the number of channels that are opened during depolarization. The increased calcium influx leads then to a positive inotropic response. The calcium channel can be identified in vitro by organic calcium channel blockers, which bind stereoselectively to a high affinity, low capacity site localized in sarcolemma and junctional sarcoplasmic reticulum. This binding site has been purified from skeletal muscle microsomes. The purified receptor contains three peptides of Mr 165, 55, and 32 kDa in stoichiometric amounts. The high affinity binding sites for dihydropyridines and phenylalkylamines are localized on the 165 kDa peptide. This peptide is phosphorylated up to 2 mol/mol by cAMP-dependent protein kinase. Reconstitution of the purified receptor yields a calcium channel that has many properties of the cardiac L-type calcium channel. It is suggested that these properties are confined to a 165 kDa peptide in skeletal muscle and to a 183 kDa peptide in cardiac muscle.
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PMID:The biochemical properties of L-type calcium channels. 246 31

The purified receptor for calcium channel blockers (CaCB-receptor) from rabbit skeletal muscle contains three polypeptides within a molecular mass of 165, 55, and 32 kDa. cAMP-dependent protein kinase was shown to phosphorylate preferentially the 165-kDa protein. The major phosphorylation site was identified and compared with the recently published primary sequence of the CaCB-receptor. It is concluded that serine 687 is the phosphorylation site. Phosphorylation of serine 687 may regulate the open-state probability of the CaCB-receptor.
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PMID:Phosphorylation of the purified CaCB-receptor. 246 77

Mouse clonal ACTH-secreting corticotrophs (AtT-20 cells) possess a membrane Ca2+-activated Cl- conductance which is partially blocked by the disulfonic stilbene derivative 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). In the current study the effect of SITS on the ACTH secretory process was evaluated. SITS markedly blocked basal and forskolin-stimulated ACTH secretion from AtT-20 cells (IC50 = 2.7 x 10(-4) M). Both CRF-induced ACTH secretion and forskolin-stimulated GH secretion from acutely dispersed rat anterior pituitary cells were inhibited by SITS (IC50 = 2.4 and 1.3 x 10(-4) M, respectively). SITS did not alter unstimulated or forskolin-elicited cAMP synthesis in AtT-20 cells, and in fact, could inhibit ACTH secretion in response to cAMP-independent agonists such as the calcium channel activator BAY-K-8644 or the protein kinase-C activator 12-tetradecanoyl-phorbol-13-acetate (IC50 = 2.6 and 2.4 x 10(-4) M, respectively). SITS did not alter the secretion of amylase from isolated exocrine pancreatic acinar cells. Its action was also fully reversible; after its removal from the incubation medium, cells secreted ACTH without a change in response to forskolin activation. Increasing extracellular Ca2+ or the addition of up to 10(-3) M tetraethylammonium or 4-aminopyridine did not reverse the inhibitory pattern of SITS action, suggesting that its inhibitory effect is most likely not due to hyperpolarization of AtT-20 cell membranes. The inability of amiloride to inhibit ACTH secretion further suggests that inhibition of ACTH secretion provoked by SITS is not due to a blockade of Cl-/HCO3- exchange. On the other hand, SITS was able to block 44% of basal 36Cl uptake by AtT-20 cells. Exchange of incubation medium chloride for gluconate or a reduction in the osmotic strength of the medium reduced both basal and secretagogue-stimulated ACTH secretion. The data suggest that SITS may modulate chloride-dependent, osmotically driven secretion from AtT-20 cells.
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PMID:4-Acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid inhibits adrenocorticotropin secretion from anterior pituitary cells. 247 34

The mechanisms by which an activator of cyclic AMP-dependent protein kinase, corticotropin releasing factor (CRF) and the protein kinase C stimulant, phorbol myristate acetate (PMA) regulate the level of intracellular free calcium in the mouse anterior pituitary cell line AtT-20 were examined using the fluorescence probe Quin 2. The increase in cytosolic calcium in AtT-20 cells induced by CRF and PMA was blocked by calcium channel antagonists indicating that both agents stimulate calcium influx. The ability of PMA to raise cytosolic calcium levels was prevented by the sodium channel antagonist tetrodotoxin, suggesting that phorbol esters depolarize the cell membrane or increase action potential frequency to enhance calcium influx. The K+ channel antagonists, tetraethylammonium, cesium and 4-aminopyridine, inhibited PMA-stimulated calcium influx in AtT-20 cells. Thus, one mechanism by which protein kinase C activation may lead to a depolarization of the cell membrane is through a reduction in K+ currents. In contrast, neither tetraethylammonium or cesium reduced CRF-stimulated calcium influx into AtT-20 cells. The stimulation of calcium influx by CRF, therefore, appears to not involve changes in K+ currents in AtT-20 cells. CRF activates cyclic AMP-dependent protein kinase to stimulate calcium influx either by facilitating calcium conductance directly or by modifying the membrane potential or firing activity of AtT-20 cells.
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PMID:Phorbol esters and corticotropin releasing factor stimulate calcium influx in the anterior pituitary tumor cell line, AtT-20, through different intracellular sites of action. 253 67


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