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)

The slow inward Ca2+ current, ICa, is fundamental in the initiation of cardiac contraction and neurohormonal regulation of cardiac function. It is increased by beta-adrenergic agonists, which stimulate synthesis of cyclic AMP (cAMP) and cAMP-dependent phosphorylation. The neurotransmitter acetylcholine reduces ICa by an unknown mechanism. There is strong evidence that acetylcholine reduces ICa by decreasing adenylate cyclase activity, but cGMP has also been implicated as ACh stimulates cGMP accumulation and activates cGMP-dependent protein kinase. Application of cGMP decreases contractile force, decreases Ca flux, shortens the duration of action potentials and inhibits Ca-dependent action potentials. Other studies, however, have concluded that cGMP levels do not correlate with contractile force and that cGMP has no effect on ICa. We have therefore examined the effects of intracellular perfusion of cGMP on ICa using isolated, voltage-clamped cells from frog ventricle. We find that cGMP has negligible effects on basal ICa, but greatly decreases the ICa that had been elevated by beta-adrenergic agonists or by intracellular perfusion with cAMP. The decrease of ICa is mediated by cAMP hydrolysis via a cGMP-stimulated cyclic nucleotide phosphodiesterase.
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PMID:Opposite effects of cyclic GMP and cyclic AMP on Ca2+ current in single heart cells. 242 89

The intracellular mechanisms by which cardiac Ca current (ICa) and the delayed outward K current (IK) are modulated during beta-adrenergic or muscarinic stimulation were investigated at the level of both single-channel and whole-cell currents in single ventricular myocytes of guinea-pigs. Superfusion of cells with beta-adrenergic agonist increased the amplitude of whole-cell ICa in a dose-dependent manner. In the single-channel recording, neither the amplitude of elementary current nor the total number of active channels was affected but the number of blank records was markedly reduced resulting in a larger amplitude of the ensemble average current. Intracellular dialysis of cells with cyclic AMP (cAMP) or the catalytic (C) subunit of cAMP-dependent protein kinase (cAMP-PK) produced a dose-dependent increase in the amplitude of ICa and IK. A non-hydrolysable ATP analogue, AMP-PNP, reduced whereas ATP gamma S enhanced the effects of beta-agonist on ICa and IK, suggesting an involvement of protein phosphorylation during the enhancement of these currents. The regulatory subunit of cAMP-PK, the heat-stable protein-kinase inhibitor (PKI) and type-1 protein phosphatase antagonized the beta-adrenergic enhancement of ICa and IK, but did not eliminate ICa. Acetylcholine (ACh) reduced the amplitude of ICa when ICa was enhanced by either beta-adrenergic agonist, forskolin or 3-isobutyl-1-methyl-xanthine but did ACh not when ICa was enhanced by intracellular dialysis with cAMP or C subunit, suggesting that muscarinic inhibition occurs at the level of adenylate cyclase. Non-hydrolysable GTP analogue, GMP-PNP, uncoupled both beta-adrenergic and muscarinic modulation of ICa. Pertussis toxin selectively eliminated the effect of ACh on ICa. Based on these results, we concluded that the activities of the Ca channel and the delayed outward K channel are controlled by the action of neurotransmitters, which are mediated by GTP-binding proteins and cAMP-dependent protein phosphorylation. It is suggested that phosphorylation of 'Ca-channel-related protein' leads to an increased open probability without changing the total number of channels or the elementary current amplitude.
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PMID:Intracellular control of calcium and potassium currents in cardiac cells. 243 80

Sympathetic neurons dissociated from the superior cervical ganglion of 2-day-old rats were studied by whole-cell patch clamp and by fura-2 measurements of the cytosolic free Ca2+ concentration, [Ca2+]i. Step depolarizations in the presence of tetrodotoxin and hexamethonium triggered two Ca2+ currents that differed in the voltage dependence of activation and kinetics of inactivation. These currents resemble the L and N currents previously described in chicken sensory neurons [Nowycky, M. C., Fox, A. P. & Tsien, R. W. (1985) Nature (London) 316, 440-442]. Treatment with acetylcholine resulted in the rapid (within seconds), selective, and reversible inhibition of the rapidly inactivated, N-type current, whereas the long-lasting L-type current remained unaffected. The high sensitivity to blocker drugs (atropine, pirenzepine) indicated that this effect of acetylcholine was due to a muscarinic M1 receptor. Intracellular perfusion with nonhydrolyzable guanine nucleotide analogs or pretreatment of the neurons with pertussis toxin had profound effects on the Ca2+ current modulation. Guanosine 5'-[gamma-thio]triphosphate caused the disappearance of the N-type current (an effect akin to that of acetylcholine, but irreversible), whereas guanosine 5'-[beta-thio]diphosphate and pertussis toxin pretreatment prevented the acetylcholine-induced inhibition. In contrast, cAMP, applied intracellularly together with 3-isobutyl-1-methylxanthine, as well as activators and inhibitors of protein kinase C, were without effect. Acetylcholine caused shortening of action potentials in neurons treated with tetraethylammonium to partially block K+ channels. Moreover, when applied to neurons loaded with the fluorescent indicator fura-2, acetylcholine failed to appreciably modify [Ca2+]i at rest but caused a partial blunting of the initial [Ca2+]i peak induced by depolarization with high K+. This effect was blocked by muscarinic antagonists and pertussis toxin and was unaffected by protein kinase activators. Thus, muscarinic modulation of the N-type Ca2+ channels appears to be mediated by a pertussis toxin-sensitive guanine nucleotide-binding protein and independent of both cAMP-dependent protein kinase and protein kinase C.
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PMID:Activation of a muscarinic receptor selectively inhibits a rapidly inactivated Ca2+ current in rat sympathetic neurons. 243 97

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

Muscarinic cholinergic agonists such as acetylcholine attenuate phosphorylation of phospholamban induced by agents that activate cAMP-dependent protein kinase. However, cAMP accumulation is variably affected or only slightly reduced; thus, the choline ester might produce effects in addition to inhibition of adenylate cyclase. We hypothesized that acetylcholine might regulate a phosphatase in mammalina myocardium. Exposure of Langendoff-perfused guinea pig ventricles to isoproterenol (10 nM) for 45 s increased phosphatase inhibitor-1 activity 2-fold. Co-administration of acetylcholine (100 nM) antagonized the effect of isoproterenol, and atropine (1 microM) blocked the effect of acetylcholine. Forskolin (1 microM) caused a 3-fold increase in inhibitor-1 activity, and acetylcholine markedly attenuated the effect of forskolin. However, acetylcholine did not lower cAMP levels in the same tissues. Both isoproterenol and forskolin reduced the type 1 phosphatase activity intrinsic to sarcoplasmic reticulum by 25-50%, using [32P]phosphorylase a or 32P-labeled membrane vesicles as a substrate for the phosphatase. Co-administration of acetylcholine markedly attenuated these effects of isoproterenol and forskolin. Acetylcholine alone caused a 50% increase in type 1 phosphatase activity. We concluded that inhibitor-1 and type 1 phosphatase can be regulated in intact cardiac muscle by agents that increase intracellular cAMP and by acetylcholine.
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PMID:Autonomic regulation of type 1 protein phosphatase in cardiac muscle. 253 94

The purpose of the present study was to determine the molecular mechanism of stimulatory actions of ACh and vasoactive intestinal polypeptide (VIP) by determining the role of various second messengers in the neurohumoral secretion. Toward such a goal, we measured cAMP, cGMP, protein kinase (PKC) activity, 3H-inositol triphosphate (3H-IP3), and 45Ca uptake in the adrenal medulla subjected to various treatments. Stimulation of splanchnic nerve endings increased 45Ca uptake, cAMP content, 3H-IP3, and PKC activity in the adrenal medulla. If muscarinic receptors of chromaffin cells were selectively activated by perfusion with muscarine, 3H-IP3 content and PKC activity were enhanced. Nicotine, on the other hand, increased only 45Ca uptake without affecting any other second messenger. Perfusion with VIP increased PKC activity and cAMP and 3H-IP3 content. None of the procedures affected cGMP content. Interplay among various second messengers was further investigated by studying interactions of nicotinic, muscarinic, and VIP-ergic receptors in modulation of catecholamine (CA) secretion and by using agents known to activate specific second messengers (e.g., forskolin, phorbol esters). Our results show that muscarine, VIP, and phorbol ester facilitated nicotine-evoked secretion by increasing PKC activity, and it was associated with an additional increase in 45Ca accumulation. On the other hand, secretion evoked by nicotine as well as muscarine was facilitated by forskolin without additional increase in 45Ca accumulation. A novel feature of the study is that ACh and VIP activate three types of receptors on chromaffin cells to stimulate and mutually facilitate the secretion of CA by generating various second messengers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cross-communication between acetylcholine and VIP in controlling catecholamine secretion by affecting cAMP, inositol triphosphate, protein kinase C, and calcium in rat adrenal medulla. 255 6

The adenylate cyclase system has been studied from the standpoint of its significance in cholinergic modulation of the synaptic transmission in the CA1 field of the rat hippocampal slices. Microionphoretic application of ACh as well as addition of either carbachol or tolbutamide (an inhibitor of cAMP-dependent protein kinase) blocked the transmission in synapses formed by the Schaffer collaterals and commissural fibres with dendrites of carbacholine both the number of releasing quanta of the neurotransmitter and the probability of their release decreased. Atropine eliminated the inhibitory effect of carbacholine on synaptic transmission. Dibutyryl cAMP and forskolin increased the amplitude of synaptic potentials and completely or partially prevented the inhibitory effect of cholinomimetics on synaptic potentials. The results obtained revealed opposite effects of cholinomimetics and activators of the adenylate cyclase system on neurotransmission in synapses formed by the Schaffer collaterals/commissural fibres and dendrites of pyramidal neurons of the hippocampal CA1 field.
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PMID:[The role of the adenyl cyclase system in cholinergic modulation of synaptic transmission in the hippocampus]. 257 80

In Xenopus laevis oocytes, adenosine and other purinergic agonists induce a K+-conductance increase that is fully mimicked by intracellular application of cAMP. Acetylcholine suppresses the K+-conductance increase caused by adenosine, by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, or by intracellular injection of cAMP. This effect of acetylcholine is not mimicked by intracellular injection of Ca2+ or of the Ca-mobilizing agent inositol 1,4,5-trisphosphate. However, adenosine and cAMP responses are inhibited by 4 beta-phorbol 12,13-dibutyrate and 4 beta-phorbol 12-myristate 13-acetate. These results suggest that, in Xenopus oocytes, the muscarinic inhibition of purinergic and cAMP responses is mediated through the activation of the phospholipid-dependent, Ca-activated protein kinase (protein kinase C).
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PMID:Acetylcholine and phorbol esters inhibit potassium currents evoked by adenosine and cAMP in Xenopus oocytes. 299 58

Cyclic GMP-dependent protein kinase (cyclic GMP-kinase) activity in isolated strips of rat aorta was measured in the absence and presence of exogenous cyclic GMP (2 microM) and expressed as a ratio. This activity ratio represented an estimate of the endogenous activation state of the enzyme. Acetylcholine [10 microM), an endothelium-dependent vasodilator, increased the activity ratio from a control value of 0.42 to 0.71 in aorta with endothelium intact. With endothelium removed, acetylcholine had no effect on cyclic GMP-kinase activity. The nitrovasodilator sodium nitroprusside (50 nM) increased activity ratios in aorta both with (0.42 to 0.54) and without (0.29 to 0.40) endothelium. Since activity ratios were higher in aortas with an intact endothelium, a tonic influence of the endothelium on aorta cyclic GMP-kinase is suggested. The vasodilator isoproterenol (3 microM) had no effect on cyclic GMP-kinase activity ratios. The increases in cyclic GMP-kinase activity caused by sodium nitroprusside and acetylcholine were preserved when aortas were homogenized in buffer containing 3 mg/ml charcoal. Thus, most of the cyclic GMP-kinase activation occurred in the intact tissue and not because of endogenous cyclic nucleotides present during homogenization or assay. The increases in the activity ratio to sodium nitroprusside and acetylcholine correlate with increases in cyclic GMP concentration and with smooth muscle relaxation. It is concluded that cyclic GMP-kinase in rat aorta is activated by acetylcholine in an endothelium-dependent manner and by sodium nitroprusside in an endothelium-independent manner. These data are consistent with the hypothesis that cyclic GMP mediates relaxation of vascular smooth muscle to acetylcholine and sodium nitroprusside by activating cyclic GMP-kinase and consequent protein phosphorylation. The data further illustrate the importance of endothelial cells in vascular responses to acetylcholine.
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PMID:Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta. 609 99

The effects of acetylcholine and sodium nitroprusside on the activity of cGMP-dependent protein kinase were studied in the perfused rat heart. Acetylcholine produced a dose-dependent increase in cGMP levels and cGMP-dependent protein kinase activity, and reduced the force of contraction. Both acetylcholine and sodium nitroprusside produced rapid increases in cardiac cGMP, with nitroprusside being the more potent agent. Only acetylcholine, however, raised the activity ratio of the cGMP-dependent protein kinase and decreased the force of contraction. Whereas acetylcholine and nitroprusside were slightly additive in their effects on total cGMP levels, the increase in the activity ratio of the cGMP-dependent protein kinase and the decrease in the force of contraction produced by acetylcholine were unchanged by nitroprusside. The results suggest that the cGMP produced by acetylcholine, but not nitroprusside, was coupled to protein kinase activation in this tissue.
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PMID:Effects of acetylcholine and nitroprusside on cGMP-dependent protein kinase in the perfused rat heart. 625 Nov 21


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