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)

beta-Adrenergic stimulation of the heart is thought to increase cardiac muscle contractility by activation of cyclic AMP-dependent protein kinase and concomitant increase in the phosphorylation of certain proteins (for refs see refs 1-6). Electrophysiological studies have shown that the stimulation of cardiac beta-adrenoreceptors, the external application of cyclic AMP or its analogues to Purkinje fibres, or the injection of cyclic AMP into single myocytes can increase the slow inward current (Isi) during the plateau phase of the action potential (AP). In heart muscle this current is mainly carried by Ca2+ (refs 10, 11) and it has been suggested that cyclic AMP-dependent phosphorylation of some component of the calcium channel increases the amount of Ca2+ which enters the cell during depolarization. We have investigated this hypothesis by examining the electrical responses of isolated guinea pig ventricular myocytes to pressure injections of subunits of the cyclic AMP-dependent protein kinase. We report here that injection of the catalytic subunit (C) resulted in a lengthening of the action potential duration (APD) and an increase in the height of the plateau as well as the amplitude of Isi. By contrast, the injection of regulatory subunit (R) shortened the APD of fast and slow response APs, an effect which was reversed by adrenaline.
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PMID:Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. 628 99

Anti-peptide antibodies specific for the neuronal calcium channel alpha 1E subunit (anti-CNE1 and anti-CNE2) were produced to study the biochemical properties and subcellular distribution of the alpha 1E polypeptide from rat brain. Immunoblotting identified a single size form of 245-255 kDa which was a substrate for phosphorylation by cAMP-dependent protein kinase, protein kinase C, cGMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase II. Ligand-binding studies of alpha 1E indicate that it is not a high affinity receptor for the dihydropyridine isradipine or the peptide toxins omega-conotoxin GVIA or omega-conotoxin MVIIC at concentrations which elicit high affinity binding to other channel types in the same membrane preparation. The alpha 1E subunit is widely distributed in the brain with the most prominent immunocytochemical staining in deep midline structures such as caudate-putamen, thalamus, hypothalamus, amygdala, cerebellum, and a variety of nuclei in the ventral midbrain and brainstem. Staining is primarily in the cell soma but is also prominent in the dendritic field of a discrete subset of neurons including the mitral cells of the olfactory bulb and the distal dendritic branches of the cerebellar Purkinje cells. Our observations indicate that the 245-255 kDa alpha 1E subunit is localized in cell bodies, and in some cases in dendrites, of a broad range of central neurons and is potentially modulated by multiple second messenger-activated protein kinase.
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PMID:Biochemical properties and subcellular distribution of the neuronal class E calcium channel alpha 1 subunit. 747 5

The effects and interactions of GnRH, TRH, a cAMP analog, a protein kinase-C (PKC) activator, a calcium ionophore, and a calcium channel blocker on pituitary glycoprotein hormone free alpha-subunit secretion and intracellular free alpha-subunit content were investigated. Treatment of dispersed rat pituitary cells with GnRH (100 nM) effected a time-dependent release of alpha-subunit, reaching a 4.5-fold increase (P < 0.05) at 24 h. Smaller effects were observed with TRH (10 nM). A rapid and progressive fall in intracellular alpha-subunit content was observed for 8 h after stimulation with GnRH (61% decrease; P < 0.05) or TRH (55% decrease; P < 0.05), which then remained constant at 24 h. The cAMP analogue 8-bromo-cAMP augmented a late release of alpha-subunit (4.5-fold increase at 24 h; P < 0.05) without affecting levels of alpha-subunit within the cells. Co-addition of 8-bromo-cAMP with GnRH or TRH arrested the marked fall in intracellular alpha-subunit seen with GnRH or TRH alone. These results suggest that although cAMP is capable of stimulating alpha-subunit secretion and maintaining cell content in the face of GnRH- and TRH-stimulated secretion, it does not mediate their effects on alpha-subunit. Like GnRH, the PKC activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) rapidly stimulated alpha-subunit secretion (1.7-fold increase at 4 h; P < 0.05) and progressively lowered cell content over 24h (73% decrease; P < 0.01). This similarity of action and the lack of demonstration of additive effects of TPA with GnRH or TRH imply a role for PKC as a mediator of GnRH and TRH action on alpha-subunit. Using verapamil (50 microM) to block L-type calcium channels had no effect on either basal or GnRH-stimulated alpha-secretion over 24 h. The calcium ionophore A23187 (3 microM) blocked the stimulatory effects of GnRH on alpha-subunit release and alone inhibited free alpha-subunit secretion (28% decrease at 24 h; P < 0.05). Our results suggest that neither cAMP nor an influx of extracellular calcium mediates the effects of GnRH or TRH on free alpha-subunit secretion. Accordingly, we postulate that PKC is involved in the actions of GnRH and TRH on alpha-subunit in rat pituitary cells, although further studies are required in PKC-depleted cells to confirm this hypothesis.
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PMID:Regulation of glycoprotein hormone free alpha-subunit secretion and intracellular alpha-subunit content in primary pituitary cells. 750 33

Activation of GnRH receptors in cultured pituitary cells and alpha T3-1 gonadotrophs caused prominent, but transient, increases in messenger RNAs for primary response genes (PRGs) including c-fos, c-jun, and junB. GnRH-induced stimulation peaked at 30 min and was dose related, with similar EC50 values (approximately 1 nM) for all three PRGs and higher maximum responses for junB than for c-jun and c-fos. The agonist-induced expression of PRGs was mimicked by activation of protein kinase-C with the phorbol ester phorbol 12-myristate 13-acetate (PMA), which acted additively with GnRH at low concentrations of both stimuli. Depletion of cellular protein kinase-C by prior treatment with PMA reduced GnRH- and PMA-induced expression of PRGs. The protein kinase-C inhibitor staurosporine also attenuated agonist- and phorbol ester-induced PRG expression. Activation of Ca2+ entry by the calcium channel agonist BayK 8644 or high K(+)-induced depolarization caused a concentration-dependent rise in intracellular Ca2+ ([Ca2+]i) and a concentration-dependent and transient expression of PRGs, albeit of smaller amplitudes than those elicited by GnRH and PMA. Ca(2+)-dependent PRG expression was abolished by the calmodulin inhibitor W-7. Parallel measurements of [Ca2+]i and steady-state levels of PRG messenger RNAs indicated that intracellular Ca2+ exerted both additive and suppressive actions over its physiological concentration range on GnRH- and PMA-induced PRG expression. At lower intracellular calcium concentrations, calcium acted additively with low concentrations of GnRH and PMA. However, high calcium concentrations suppressed high agonist- and phorbol ester-induced PRG expression. In contrast, omission of Ca2+ from the extracellular medium significantly enhanced induction of PRGs. These findings indicate that GnRH-induced PRG expression in gonadotrophs is mediated by protein kinase-C and calcium, and that protein kinase-C-dependent induction of PRGs is modulated both positively and negatively by physiological changes in [Ca2+]i. Such coordinate actions of the two signaling molecules provide a mechanism for the control of PRG expression by preferential integration of low strength, and attenuation of high strength, extracellular signals.
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PMID:Coordinate actions of calcium and protein kinase-C in the expression of primary response genes in pituitary gonadotrophs. 751 88

We examined the effect of several inhibitors/activators of various protein kinases on the proliferation and apoptosis of nontransformed rat coronary vascular smooth muscle cells (SMC). As expected, all the compounds (calphostin C, KT5720, KT5823, verapamil, W7, and dibutyryl-cAMP) inhibited SMC proliferation, as judged by [3H]thymidine incorporation. Three (calphostin C, verapamil and dibutyryl-cAMP) of the six compounds caused occurrence of the classical apoptotic morphology in SMC. The effect of calphostin C, an inhibitor of protein kinase C, was examined in more detail due to the known involvement of this kinase in regulation of apoptosis in a variety of cell types. In SMC cultures exposed for 1, 2, and 3 days to 0.1 mumol/L calphostin C, 7 +/- 1%, 32 +/- 3%, and 29 +/- 3% of cells underwent apoptosis, respectively, as assessed by cell morphology (control cultures had 1 to 3% of apoptotic cells). The effect of calphostin C was transient in that on day 6 following exposure to this compound the number of apoptotic cells declined to control values. Simultaneous with the induction of apoptotic morphology in SMC, a decline was seen (within 24 hours) in expression of the oncoprotein Bcl-2 in morphologically nonapoptotic SMC. An altered distribution of Bcl-2 was seen in the apoptotic cells. The calphostin C-induced generation of apoptotic cells in SMC cultures and the decline/alteration of Bcl-2 expression were not accompanied by degradation of DNA into nucleosomal fragments. In conclusion, normal, nontransformed rat coronary artery vascular SMC undergo apoptosis when exposed to an inhibitor of protein kinase C (calphostin C), to a calcium channel blocker (verapamil), and to a stimulator of cAMP-dependent protein kinase (dibutyryl-cAMP). The induction of apoptosis by the inhibitor of protein kinase C is accompanied by alterations in the Bcl-2 expression but not by DNA fragmentation.
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PMID:Apoptosis of vascular smooth muscle cells. Protein kinase C and oncoprotein Bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells. 752 16

The principal (alpha 1) subunit of purified skeletal muscle dihydropyridine-sensitive (L-type) calcium channels is present in full-length (212 kDa) and COOH-terminal truncated (190 kDa) forms, which are both phosphorylated by cAMP-dependent protein kinase (cA-PK) in vitro. Immunoprecipitation of the calcium channel from rabbit muscle myotubes in primary cell culture followed by phosphorylation with cA-PK, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and two-dimensional phosphopeptide mapping revealed comparable phosphorylation of three COOH-terminal phosphopeptides found in the purified full-length alpha 1 subunit. Stimulation of muscle myotubes with a permeant cAMP analogue, 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate, prior to immunoprecipitation of alpha 1 results in a 60-80% reduction of cA-PK catalyzed "back" phosphorylation of each of these sites in vitro in calcium channels purified from the cells, indicating that these sites are phosphorylated in vivo in response to increased intracellular cAMP. Serine 687, the most rapidly phosphorylated site in the truncated 190-kDa alpha 1 subunit, was observed as a minor phosphopeptide whose level of phosphorylation was not significantly affected by stimulation of endogenous cA-PK in the myotubes. The COOH-terminal sites, designated tryptic phosphopeptides 4, 5, and 6, were identified as serine 1757 (phosphopeptides 4 and 6) and 1854 (phosphopeptide 5) by a combination of protease cleavage, phosphorylation of synthetic peptides and fusion proteins, specific immunoprecipitation, and phosphopeptide mapping. Phosphorylation of serines 1757 and 1854 in the COOH-terminal region of the 212-kDa alpha 1 subunit in intact skeletal muscle cells may play a pivotal role in the regulation of calcium channel function by cA-PK.
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PMID:Sites of selective cAMP-dependent phosphorylation of the L-type calcium channel alpha 1 subunit from intact rabbit skeletal muscle myotubes. 760 7

The effects of parathyroid hormone (PTH) on sodium homeostasis in the distal tubule are not well defined. Using A6 cells as a model for distal tubular epithelium we measured equivalent short circuit current (leq), as an estimate of net sodium transport. We found that PTH increased leq in a dose-dependent manner. DDA, an agent which inhibits adenylate cyclase, decreased PTH-activated sodium transport, suggesting a role for cAMP elevation in PTH effects. Moreover, addition of Rp-cAMP, an inhibitor of cAMP-dependent protein kinase, partially blocked the PTH-stimulated leq. PTH also elicited a sustained increase in [Ca2+]i in A6 cells. This elevation in [Ca2+]i was abolished by removal of calcium from the extracellular medium, suggesting the involvement of calcium influx pathways. In fact, addition of the calcium channel blocker nitrendipine to PTH-stimulated leq partially blocked PTH-activated sodium transport. Taken together these data demonstrate that PTH stimulates electrogenic sodium transport in A6 cells and that this effect may be mediated through a rise in both intracellular calcium and cellular cAMP.
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PMID:Parathyroid hormone stimulates electrogenic sodium transport in A6 cells. 764 25

In dispersed acini from rat pancreas, verapamil (a phenylalkylamine calcium channel blocker) potentiated amylase secretion stimulated by vasoactive intestinal peptide (VIP), secretin, peptide histidine isoleucine, helodermin, forskolin, and 8-bromocyclic AMP. The action of verapamil on VIP-stimulated amylase secretion was detectable at 10 microM verapamil and maximal at 100 microM verapamil. Verapamil did not alter binding of 125I-VIP, basal cAMP, the increase in cAMP caused by VIP, or the increase in cAMP-dependent protein kinase caused by VIP. The effects of verapamil on stimulated amylase secretion were fully reversible and could be reproduced by nicardipine (a 1,4-dihydropyridine calcium channel blocker) and diltiazem (a benzothiazepine calcium channel blocker), but not by cinnarizine (a piperazine calcium channel blocker). Although 300 microM verapamil increased outflux of 45Ca, 100 microM verapamil, the concentration that produced maximal potentiation of VIP-stimulated amylase secretion, did not alter 45Ca outflux. Our results indicate that the action of verapamil to potentiate amylase secretion stimulated by secretagogues that activate the cAMP pathway occurs at a step that is distal to the activation of cAMP-dependent protein kinase.
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PMID:Effect of verapamil on the cyclic AMP-mediated pathway for amylase secretion in rat pancreatic acini. 768 80

Treatment with 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) (1-12 h, 10(-10) M) stimulates DNA synthesis in proliferating myoblasts, with an early response at 2-4 h of treatment followed by a maximal effect at 10 h. To investigate the mechanism involved in the mitogenic action of the hormone we studied the possible activation of intracellular messengers by 1,25(OH)2D3. The initial phase of stimulation of [3H]thymidine incorporation into DNA by the sterol was mimicked by the protein kinase C activator tetradecanoylphorbol acetate (TPA) in a manner which was dose dependent and specific as the inactive analog 4 alpha-phorbol was without effect. Maximal responses to TPA (100 nM) were obtained at 4 h. Staurosporine, a protein kinase C inhibitor, blocked the effect of 1,25(OH)2D3 on myoblast proliferation at 4 h. In addition, a fast (1-5 min) elevation of diacylglycerol levels and membrane-associated protein kinase C activity was observed in response to 1,25(OH)2D3. The adenylate cyclase activator forskolin (20 microM) and dibutyryl-cAMP (50 microM) increased DNA synthesis reproducing the second 1,25(OH)2D3-dependent stimulatory phase at 10 h. Inhibitors of protein kinase A blocked the increase in muscle cell DNA synthesis induced by 1,25(OH)2D3 at 10 h. Significant increases in cyclic AMP levels were detected in myoblasts treated with the sterol for 1-10 h. The calcium channel antagonist nifedipine (5-10 microM) abolished both the effects of 4-h treatment with 1,25(OH)2D3 or TPA and 10-h treatment with 1,25(OH)2D3 or dibutyryl-cAMP. Similar to the calcium channel agonist Bay K8644, 1,25(OH)2D3 stimulated myoblast 45Ca uptake and its effects were blocked by nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for the participation of protein kinase C and 3',5'-cyclic AMP-dependent protein kinase in the stimulation of muscle cell proliferation by 1,25-dihydroxy-vitamin D3. 768 42

It is well established that the inotropic effect of beta-adrenergic agonists is mediated by the stimulation of adenylyl cyclase activity and the subsequent phosphorylation of specific proteins by cAMP-dependent protein kinase. The L-type calcium channel is believed to be one of the proteins phosphorylated; the phosphorylation of calcium channels is believed to increase calcium entry into myocytes, which is, at least in part, responsible for the positive inotropic effect. The present studies show that the cAMP-elevating effect of isoproterenol is increased as extracellular calcium is lowered and that calcium channel blockers potentiate the cAMP-elevating effect of isoproterenol in the presence in extracellular calcium. This effect is not dependent on effects on cAMP catabolism and is not specific for beta-adrenergic receptors, because the cAMP-elevating effect of forskolin is similarly affected. Measurements of adenylyl cyclase activity in cardiac membranes show that submicromolar Ca2+ concentrations directly inhibit adenylyl cyclase activity. These results demonstrate that increased entry of Ca2+ via L-type calcium channels in response to beta-adrenergic receptor stimulation acts as a negative regulator of the effect of beta receptor stimulation on adenylyl cyclase activity.
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PMID:Calcium entry via L-type calcium channels acts as a negative regulator of adenylyl cyclase activity and cyclic AMP levels in cardiac myocytes. 769 67


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