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 properties and roles of ATP-sensitive (KATP) and inwardly rectifying (KIR) potassium channels are reviewed. Potassium channels regulate the membrane potential of smooth muscle, which controls calcium entry through voltage-dependent calcium channels, and thereby contractility through changes in intracellular calcium. The KATP channel is likely to be composed of members of the inward rectifier channel gene family (Kir6) and sulfonylurea receptor proteins. The KIR channels do not appear to be as widely distributed as KATP channels in smooth muscle and may provide a mechanism by which changes in extracellular K+ can alter smooth muscle membrane potential, and thereby arterial diameter. The KATP channels contribute to the resting membrane conductance of some types of smooth muscle and can open under situations of metabolic compromise. The KATP channels are targets of a wide variety of vasodilators and constrictors, which act, respectively, through adenosine 3',5'-cyclic monophosphate/protein kinase A and protein kinase C. The KATP channels are also activated by a number of synthetic vasodilators (e.g., diazoxide and pinacidil) and are inhibited by the oral hypoglycemic sulfonylurea drugs (e.g., glibenclamide). Together, KATP and KIR channels are important regulators of smooth muscle function and represent important therapeutic targets.
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PMID:ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. 935 14

Glutamate, the neurotransmitter released by photoreceptors, excites horizontal cells and OFF-type bipolar cells by activating ionotropic receptors. This study investigated an additional action of glutamate in which it modulates a voltage-gated ion channel in horizontal cells. We find that glutamate and APB (2-amino-4-phosphonobutyrate) produce a delayed and moderately prolonged suppression of an inward rectifier current (IRK+). This effect is proposed to occur via an APB-sensitive metabotropic glutamate receptor (mGluR) because common agonists for the ionotropic or APB-insensitive mGluRs are ineffective and the APB-insensitive receptor antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) does not block the actions of glutamate or APB. 8-Br-cGMP, 1-methyl-3-isobutylxanthine (IBMX), and atrial natriuretic peptide (ANP) but not 8-Br-cAMP mimic the suppression of IRK+. The effects of glutamate and APB are blocked by protein kinase inhibitors including Rp-8-pCPT-cGMPS, H-8, and H-7 as well as by ATPgammaS. We hypothesize that the APB receptor suppresses IRK+ via upregulation of cGMP and subsequent activation of a cGMP-dependent protein kinase. This pathway is likely regulated by an ATP-dependent phosphorylation. This is a novel signaling pathway for mGluRs and indicates that at least two distinct APB-activated pathways exist in the retina. Functionally, this APB receptor-mediated action found in horizontal cells would provide a means by which spatially restricted changes of glutamate, produced by local illumination of photoreceptors, could regulate IRK+ and consequently the response properties of these neurons. This would serve to adapt selectively retinal regions stimulated by small regions of the visual world.
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PMID:Metabotropic glutamate receptor-mediated suppression of an inward rectifier current is linked via a cGMP cascade. 936 42

The effect of dopamine (DA) was investigated on acutely dissociated rat substantia nigra pars compacta (SNc) neurones by using patch clamp recording. The SNc neurones could be classified into two groups. About 75% of large neurones (>30 microm in diameter) were tyrosine hydroxylase (TH) positive while almost all small neurones (<20 microm) were TH negative. In the large neurones, DA hyperpolarized the membrane, resulting in a reduction of the frequency of spontaneous action potentials in current-clamp mode and induced an inward rectifier K+ current in voltage-clamp mode. Quinpirole, a D2 receptor agonist, mimicked the DA action. S(-)-sulpiride, a D2 receptor antagonist, inhibited the DA-induced current (I(DA)) more effectively than SKF83566, a D1 receptor antagonist. Intracellular application of either guanosine 5'-O-(2-thiodiphosphate) (GDP-betaS) or pertussis toxin (IAP) suppressed I(DA). Guanosine 5'-O-(3-thiotriphosphate) (GTP-gammaS) sustained the DA response. Modulators for cAMP such as forskolin and isobutylmethylxathine, H-89, a protein kinase A inhibitor, and chelerythrine, a protein kinase C inhibitor, had no effect on I(DA). The frequency of DA-induced single channel currents in the inside-out patch configuration, for which the unitary conductance was 56.6pS, was greatly reduced by the replacement of GTP with GDP perfused at the cytosolic side. These results suggest that DA acts on a D2-like receptor and activates directly an IAP-sensitive G protein coupled with inward rectifier K+ channels, resulting in a decrease in the spontaneous firing activities of rat SNc dopaminergic neurones.
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PMID:Dopamine activates inward rectifier K+ channel in acutely dissociated rat substantia nigra neurones. 1067 Apr 14

Properties of the 5-hydroxytryptamine (5-HT)-induced current (I(5-HT)) were examined in neurons of rat dorsolateral septal nucleus (DLSN) by using whole cell patch-clamp techniques. I(5-HT) was associated with an increase in the membrane conductance of DLSN neurons. The reversal potential of I(5-HT) was -93 +/- 6 (SE) mV (n = 7) in the artificial cerebrospinal fluid (ACSF) and was changed by 54 mV per decade change in the external K(+) concentration, indicating that I(5-HT) is carried exclusively by K(+). Voltage dependency of the K(+) conductance underlying I(5-HT) was investigated by using current-voltage relationship. I(5-HT) showed a linear I-V relation in 63%, inward rectification in 21%, and outward rectification in 16% of DLSN neurons. (+/-)-8-Hydroxy-dipropylaminotetralin hydrobromide (30 microM), a selective 5-HT(1A) receptor agonist, also produced outward currents with three types of voltage dependency. Ba(2+) (100 microM) blocked the inward rectifier I(5-HT) but not the outward rectifier I(5-HT). In I(5-HT) with linear I-V relation, blockade of the inward rectifier K(+) current by Ba(2+) (100 microM) unmasked the outward rectifier current in DLSN neurons. These results suggest that I(5-HT) with linear I-V relation is the sum of inward rectifier and outward rectifier K(+) currents in DLSN neurons. Intracellular application of guanosine-5'-O-(3-thiotriphosphate) (300 microM) and guanosine-5'-O-(2-thiodiphosphate) (5 mM), blockers of G protein, irreversibly depressed I(5-HT). Protein kinase C (PKC) 19-36 (20 microM), a specific PKC inhibitor, depressed the outward rectifier I(5-HT) but not the inward rectifier I(5-HT). I(5-HT) was depressed by N-ethylmaleimide, which uncouples the G-protein-coupled receptor from pertussis-toxin-sensitive G proteins. H-89 (10 microM) and adenosine 3',5'-cyclic monophosphothioate Rp-isomer (300 microM), protein kinase A inhibitors, did not depress I(5-HT). Phorbol 12-myristate 13-acetate (10 microM), an activator of PKC, produced an outward rectifying K(+) current. These results suggest that both 5-HT-induced inward and outward rectifying currents are mediated by a G protein and that PKC is probably involved in the transduction pathway of the outward rectifying I(5-HT) in DLSN neurons.
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PMID:Characterization of outward currents induced by 5-HT in neurons of rat dorsolateral septal nucleus. 1128 69

Effects of endothelin-1 (ET-1) on the L-type calcium current (ICa) and delayed rectifier potassium current (IK) were studied in isolated canine ventricular cardiomyocytes using the whole-cell configuration of the patch-clamp technique. ET-1 (8 nM) was applied in three experimental arrangements: untreated cells, in the presence of 50 nM isoproterenol, and in the presence of 250 microM 8-bromo-cAMP. In untreated cells, ET-1 significantly decreased the peak amplitude of ICa by 32.3+/-4.8% at +5 mV (P<0.05) without changing activation or inactivation characteristics of ICa. ET-1 had no effect on the amplitude of IK, Ito (transient outward current) or IK1 (inward rectifier K current) in untreated cells; however, the time course of recovery from inactivation of Ito was significantly increased by ET-1 (from 26.5+/-4.6 ms to 59.5+/- 1.8 ms, P < 0.05). Amplitude and time course of intracellular calcium transients, recorded in voltage-clamped cells previously loaded with the fluorescent calcium indicator dye Fura-2, were not affected by ET-1. ET-1 had no effect on force of contraction in canine ventricular trabeculae. Isoproterenol increased the amplitude of ICa to 263+/-29% of control. ET-1 reduced ICa also in isoproterenol-treated cells by 17.8+/-2% (P<0.05); this inhibition was significantly less than obtained in untreated cells. IK was increased by isoproterenol to 213+/-18% of control. This effect of isoproterenol on IK was reduced by 31.8+/-4.8% if the cells were pretreated with ET-1. Similarly, in isoproterenol-treated cells ET-1 decreased IK by 16.2+/-1.5% (P<0.05). Maximal activation of protein kinase A (PKA) was achieved by application of 8-bromo-cAMP in the pipette solution. In the presence of 8-bromo-cAMP ET-1 failed to alter ICa or IK It was concluded that differences in effects of ET-1 on ICa and IK may be related to differences in cAMP sensitivity of the currents.
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PMID:Different effects of endothelin-1 on calcium and potassium currents in canine ventricular cells. 1133 Mar 31

Phosphorylation-dependent events have been shown to modulate the activity of several members of the mammalian CLC Cl- channel gene family, including the inward rectifier ClC-2. In the present study we investigated the regulation of rat ClC-2 expressed in the TSA-201 cell line (a transformed HEK293 cell line that stably expresses the SV40 T-antigen) by protein kinases. Protein kinase A activation phosphorylated ClC-2 in vivo, whereas stimulation of protein kinase C with phorbol 12-myristate 13-acetate did not. In vitro labeling studies confirmed that protein kinase A could directly phosphorylate ClC-2, and that protein kinase C and Ca2+/calmodulin-dependent protein kinase II did not. Nevertheless, protein kinase A-dependent phosphorylation of CLC-2 failed to regulate either the magnitude or the kinetics of the hyperpolarization-activated Cl- currents. Considered together, we demonstrate that protein kinase A activation results in the phosphorylation of rat ClC-2 in vivo, but this event is independent of Cl- channel activity.
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PMID:Protein kinase A activation phosphorylates the rat ClC-2 Cl- channel but does not change activity. 1142 97

Genistein, a soybean-derived isoflavone with an inhibitory effect on protein tyrosine kinases (PTKs), has been shown to suppress osteoclastic bone resorption. To clarify the mechanisms underlying this action, we investigated the effects of genistein on inward rectifier K(+) current (I(Kir)) in rat osteoclasts by using the whole-cell patch-clamp technique. Extracellularly applied genistein inhibited I(Kir) in a concentration-dependent manner. Physiologically attainable concentrations of genistein inhibited I(Kir). IC(50) values obtained 5 and 10 min after the application of genistein were 54 and 27 microM, respectively. The removal of genistein partially restored the current. Daidzein, an isoflavone without PTK-inhibiting activity, also showed a weak inhibitory effect on I(Kir), but genistin had no effect. Other PTK inhibitors, tyrphostin A25, tyrphostin B42, and tyrphostin B46, inhibited I(Kir), whereas herbimycin A and lavendustin A were without effect. The inactive tyrphostin, A1, showed a similar inhibitory effect as tyrphostin A25. The tyrosine phosphatase inhibitor, orthovanadate, did not affect the inhibitory potency of genistein on I(Kir). The inhibitory action of genistein was unaffected by changing intracellular Ca(2+) concentration ([Ca(2+)]i) or by pretreatment of the cell with GDPbetaS, Rp-cAMPS, okadaic acid, or staurosporine. Therefore the inhibition of I(Kir) by genistein does not depend on PTK inhibition, involvement of changes in [Ca(2+)]i, or secondary interaction with protein kinase A or protein kinase C. Genistein-induced inhibition of I(Kir) would cause membrane depolarization, elevation of [Ca(2+)]i, and inhibition of osteoclastic bone resorption.
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PMID:Genistein, a soybean isoflavone, inhibits inward rectifier K(+) channels in rat osteoclasts. 1156 87

Presynaptic metabotropic glutamate receptors (mGluRs) often act as feedback inhibitors of synaptic transmission and serve important roles in defining the activity of glutamatergic synapses. Recent investigations have begun to identify novel interactions of presynaptic mGluRs, especially mGluR7, with multiple protein kinases and putative regulatory proteins that probably serve to further shape the overall activity of glutamatergic synapses. In the present study, we report that in addition to protein kinase C (PKC), cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) can inhibit calmodulin (CaM) interactions with the carboxyl-terminal tail of mGluR7. These actions are mediated by PKC-, PKA-, or PKG-dependent phosphorylation of mGluR7 at a single serine residue, Ser(862), in the carboxyl terminus of the receptor. Mutation of this residue inhibits kinase-mediated phosphorylation of the mGluR7 carboxyl terminus and reverses kinase-mediated inhibition of CaM binding to mGluR7. However, PKC-mediated inhibition of the functional coupling of mGluR7 to G protein-coupled inward rectifier potassium (GIRK) currents in a heterologous expression system is not affected by mutating Ser(862). Furthermore, mutation of Ser(862) to glutamate to mimic receptor phosphorylation and inhibit CaM interactions with mGluR7 does not affect receptor function. These studies demonstrate that the ability of these second messenger-dependent kinases to inhibit mGluR7-mediated activation of GIRK current is not dependent on the phosphorylation of Ser(862) or the regulation of CaM binding to mGluR7. Furthermore, our studies suggest that CaM binding is not required for mGluR7-mediated activation of GIRK current.
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PMID:Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function. 1202 91

In excitable cells, receptor-induced Ca(2+) release from intracellular stores is usually accompanied by sustained depolarization of cells and facilitated voltage-gated Ca(2+) influx (VGCI). In quiescent pituitary lactotrophs, however, endothelin-1 (ET-1) induced rapid Ca(2+) release without triggering Ca(2+) influx. Furthermore, in spontaneously firing and depolarized lactotrophs, the Ca(2+)-mobilizing action of ET-1 was followed by inhibition of spontaneous VGCI caused by prolonged cell hyperpolarization and abolition of action potential-driven Ca(2+) influx. Agonist-induced depolarization of cells and enhancement of VGCI upon Ca(2+) mobilization was established in both quiescent and firing lactotrophs treated overnight with pertussis toxin (PTX). Activation of adenylyl cyclase by forskolin and addition of cell-permeable 8-bromo-cAMP did not affect ET-1-induced sustained inhibition of VGCI, suggesting that the cAMP-protein kinase A signaling pathway does not mediate the inhibitory action of ET-1 on VGCI. Consistent with the role of PTX-sensitive K(+) channels in ET-1-induced hyperpolarization of control cells, but not PTX-treated cells, ET-1 decreased the cell input resistance and activated a 5 mM Cs(+)-sensitive K(+) current. In the presence of Cs(+), ET-1 stimulated VGCI in a manner comparable with that observed in PTX-treated cells, whereas E-4031, a specific blocker of ether-a-go-go-related gene-like K(+) channels, was ineffective. Similar effects of PTX and Cs(+) were also observed in GH(3) immortalized cells transiently expressing ET(A) receptors. These results indicate that signaling of ET(A) receptors through the G(i/o) pathway in lactotrophs and the subsequent activation of inward rectifier K(+) channels provide an effective and adenylyl cyclase-independent mechanism for a prolonged uncoupling of Ca(2+) mobilization and influx pathways.
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PMID:Ca(2+)-mobilizing endothelin-A receptors inhibit voltage-gated Ca(2+) influx through G(i/o) signaling pathway in pituitary lactotrophs. 1202 94

The Kir1.1 (ROMK) subtypes of inward rectifier K+ channels mediate potassium secretion and regulate sodium chloride reabsorption in the kidney. The density of ROMK channels on the cortical collecting duct apical membrane is exquisitely regulated in concert with physiological demands. Although protein kinase A-dependent phosphorylation of one of the three phospho-acceptors in Kir1.1, Ser-44, also a canonical serum-glucocorticoid-regulated kinase (SGK-1) phosphorylation site, controls the number of active channels, it is unknown whether this involves activating dormant channels already residing on the plasma membrane or recruiting new channels to the cell surface. Here we explore the mechanism and test whether SGK-1 phosphorylation of ROMK regulates cell surface expression. Removal of the phosphorylation site by point mutation (Kir1.1, S44A) dramatically attenuated the macroscopic current density in Xenopus oocytes. As measured by antibody binding of external epitope-tagged forms of Kir1.1, surface expression of Kir1.1 S44A was inhibited, paralleling the reduction in macroscopic current. In contrast, surface expression and macroscopic current density was augmented by a phosphorylation mimic mutation, Kir1.1 S44D. In vitro phosphorylation assays revealed that Ser-44 is a substrate of SGK-1 phosphorylation, and expression of SGK-1 with the wild type channel increased channel density to the same level as the phosphorylation mimic mutation. Moreover, the stimulatory effect of SGK-1 was completely abrogated by mutation of the phosphorylation site. In conclusion, SGK-1 phosphorylation of Kir1.1 drives expression on the plasmalemma. Because SGK-1 is an early aldosterone-induced gene, our results suggest a possible molecular mechanism for aldosterone-dependent regulation of the secretory potassium channel in the kidney.
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PMID:Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A. 1268 16


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