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)

Activation of adenosine A1 receptors raised spike thresholds and induced a dissociation of excitatory postsynaptic potential (EPSP) spike coupling in hippocampal pyramidal neurones. This effect could be prevented by activation of A2A adenosine receptors. The A1 receptor agonist N6-cyclopentyladenosine caused a dissociation of the EPSP spike coupling recorded extracellularly and increased the threshold for spike generation measured intracellularly. These effects were prevented by the A2A receptor agonist CGS21680. A series of agents interfering with adenylate cyclase activity, protein kinase A or C, or nitric oxide synthase had no effect on these responses to N6-cyclopentyladenosine. Superfusion with barium or glibenclamide prevented both the dissociation of EPSP spike coupling and the increase of spike threshold. It is concluded that a barium- and glibenclamide-sensitive potassium current may be involved in the postsynaptic effects of A1 receptors on spike threshold, and it is suggested that a similar suppression of a potassium current by A2A receptors could underlie the inhibition of A1 receptor responses.
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PMID:Barium, glibenclamide and CGS21680 prevent adenosine A1 receptor changes of ES coupling and spike threshold. 1562 19

The hyperpolarizing receptor potential of ciliary photoreceptors of scallop and other mollusks is mediated by a cGMP-activated K conductance; these cells also express a transient potassium current triggered by depolarization. During steady illumination, the outward currents elicited by voltage steps lose their decay kinetics. One interesting conjecture that has been proposed is that the currents triggered by light and by depolarization are mediated by the same population of channels, and that illumination evokes the receptor potential by removing their steady-state inactivation. Exploiting the information that has become available on the phototransduction cascade of ciliary photoreceptors, we demonstrated that the same downstream signaling elements are implicated in the modulation of voltage-elicited currents: direct chemical stimulation both at the level of the G protein and of the final messenger that controls the light-dependent channels (cGMP) also attenuate the falling phase of the voltage-activated current. Application of a protein kinase G antagonist was ineffective, suggesting that a cGMP-initiated phosphorylation step is not implicated. To ascertain the commonality of ionic pathways we used pharmacological blockers. Although millimolar 4-aminopyridine (4-AP) suppressed both currents, at micromolar concentrations only the photocurrent was blocked. Conversely, barium completely and reversibly antagonized the transient voltage-activated current with no detectable effect on the light-evoked current. These results rule out that the same ionic pores mediate both currents; the mechanism of light modulation of the depolarization-evoked K current was elucidated as a time-dependent increase in the light-sensitive conductance that is superimposed on the inactivating K current.
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PMID:On the gating mechanisms of the light-dependent conductance in Pecten hyperpolarizing photoreceptors: does light remove inactivation in voltage-dependent K channels? 1582 93

K(+) channels play an important role in pump-leak coupling and volume regulation in the renal proximal tubule. Previous experiments have identified a barium-sensitive K(+) conductance (G(Ba)) in proximal tubule cells isolated from frog kidneys. In this paper we examine the regulation of G(Ba) by ATP. G(Ba) was measured in single cells isolated from frog kidney using the whole-cell patch-clamp technique. G(Ba) was activated by 2 mM: intracellular ATP. This activation was enhanced by inhibition of protein kinase C and attenuated by inhibition of protein kinase A, indicating reciprocal regulation by these kinases. Activation by ATP was reduced in the presence of a hypertonic bath solution, suggesting that cell swelling was required. However, after activation to steady-state, G(Ba )was not sensitive to cell-volume changes. Hypotonic shock-induced volume regulation was inhibited by barium and quinidine, inhibitors of G(Ba). The effect of maximal inhibitory concentrations of barium and quinidine on volume regulation was similar and addition of both blockers together did not augment the inhibitory response. G(Ba) was also activated by ADP, via a mechanism dependent on the presence of Mg(2+). However, the responses to ADP and ATP were not additive, suggesting that these nucleotides may share a common mechanism of activation. The regulation of G(Ba) by ATP was biphasic, with a half-maximal activating concentration of 0.89 mM and a half maximal inhibitory concentration of 6.71 mM. The sensitivity to nucleotides suggests that G(Ba) may be regulated by the metabolic state of the cell. Furthermore, the sensitivity to solution osmolality, coupled with the blocker profile of inhibition of volume regulation, suggests that G(Ba) could play a role in volume regulation.
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PMID:Mechanisms underlying regulation of a barium-sensitive K+ conductance by ATP in single proximal tubule cells isolated from frog kidney. 1600 2

In Drosophila, protein kinase CK2 regulates a diverse array of developmental processes. One of these is cell-fate specification (neurogenesis) wherein CK2 regulates basic-helix-loop-helix (bHLH) repressors encoded by the Enhancer of Split Complex (E(spl)C). Specifically, CK2 phosphorylates and activates repressor functions of E(spl)M8 during eye development. In this study we describe the interaction of CK2 with an E(spl)-related bHLH repressor, Deadpan (Dpn). Unlike E(spl)-repressors which are expressed in cells destined for a non-neural cell fate, Dpn is expressed in the neuronal cells and is thought to control the activity of proneural genes. Dpn also regulates sex-determination by repressing sxl, the primary gene involved in sex differentiation. We demonstrate that Dpn is weakly phosphorylated by monomeric CK2alpha, whereas it is robustly phosphorylated by the embryo-holoenzyme, suggesting a positive role for CK2beta. The weak phosphorylation by CK2alpha is markedly stimulated by the activator polylysine to levels comparable to those with the holoenzyme. In addition, pull down assays indicate a direct interaction between Dpn and CK2. This is the first demonstration that Dpn is a partner and target of CK2, and raises the possibility that its repressor functions might also be regulated by phosphorylation.
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PMID:Drosophila CK2 phosphorylates Deadpan, a member of the HES family of basic-helix-loop-helix (bHLH) repressors. 1634 13

L-type Ca2+ channel activity was measured in L6 cells as nifedipine-sensitive barium (Ba2+; 5 mM) influx in a depolarizing salt solution containing 140 mM KCl. Addition of AVP (arginine-vasopressin) during Ba2+ uptake reduced the rate of Ba2+ influx by 60-100%; this was followed by a gradual restoration of the initial rate of Ba2+ uptake. Blockade of PKC (protein kinase C) by pretreatment with 10 muM bisindolylmaleimide did not affect the initial inhibition of Ba2+ influx, but completely abolished the recovery phase. The effect of AVP was half-maximal at 10 nM AVP and was blocked by the V1a receptor antagonist d-(CH2)(5)-Tyr(Me)-AVP. Activation of G(alphas) by isoprenaline or cholera toxin antagonized the actions of AVP on Ba2+ uptake. This protection persisted in the presence of the PKA (protein kinase A) inhibitor KT5720, and was not mimicked by agents that increase cAMP. Inhibition of Ba2+ influx was also elicited by ATP and ET (endothelin 1) with an order of effectiveness ET<ATP<AVP. Each of these agents has been reported to act through G(q)-coupled receptors. We conclude that activation of G(q)-coupled receptors produces a rapid inhibition of the cardiac L-type Ca2+ channel, which is subsequently overcome by activation of PKC.
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PMID:Regulation of the cardiac L-type calcium channel in L6 cells by arginine-vasopressin. 1691 57

Lateral inhibition is critical for cell fate determination and involves the functions of Notch (N) and its effectors, the Enhancer of Split Complex, E(spl)C repressors. Although E(spl) proteins mediate the repressive effects of N in diverse contexts, the role of phosphorylation was unclear. The studies we describe implicate a common role for the highly conserved Ser/Thr protein kinase CK2 during eye and bristle development. Compromising the functions of the catalytic (alpha) subunit of CK2 elicits a rough eye and defects in the interommatidial bristles (IOBs). These phenotypes are exacerbated by mutations in CK2 and suppressed by an increase in the dosage of this protein kinase. The appearance of the rough eye correlates, in time and space, to the specification and refinement of the 'founding' R8 photoreceptor. Consistent with this observation, compromising CK2 elicits supernumerary R8's at the posterior margin of the morphogenetic furrow (MF), a phenotype characteristic of loss of E(spl)C and impaired lateral inhibition. We also show that compromising CK2 elicits ectopic and split bristles. The former reflects the specification of excess bristle SOPs, while the latter suggests roles during asymmetric divisions that drive morphogenesis of this sensory organ. In addition, these phenotypes are exacerbated by mutations in CK2 or E(spl), indicating genetic interactions between these two loci. Given the centrality of E(spl) to the repressive effects of N, our studies suggest conserved roles for this protein kinase during lateral inhibition. Candidates for this regulation are the E(spl) repressors, the terminal effectors of this pathway.
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PMID:Drosophila CK2 regulates lateral-inhibition during eye and bristle development. 1693 Sep 55

The role of C-type natriuretic peptide (CNP) in the gastrointestinal tract is still unclear. This study was designed to investigate the effect of CNP on barium current (I(Ba)) through the L-type calcium channel in gastric antral myocytes of guinea pigs. The whole-cell patch clamp technique was performed in gastric antral myocytes isolated by collagenase in guinea pigs. CNP significantly inhibited I(Ba) in a dose-dependent manner at the concentrations of 0.001, 0.01, and 0.1 micromol/l, CNP inhibited I(Ba) to 81.56 +/- 2.48 %, 73.64 +/- 3.65 %, and 57.77 +/- 4.93 % of control at 0 mV, respectively. The values of steady-state half-inactivation voltage (33.6 +/- 2.6 mV and 33.8 +/- 3.4 mV, in control and CNP groups, respectively) or the half-activation voltage (-12.6 +/- 2.2 mV and 12.4 +/- 1.8 mV) of I(Ba) were not significantly changed (p > 0.05, n = 6). 8-br-cGMP (1 mmol/l) mimicked the effect of CNP on I(Ba), and the peak current of I(Ba) was inhibited from -403.84 +/- 61.87 pA to 318.94 +/- 67.17 pA (p < 0.05, n = 5). In the presence of LY83583 (0.1 micromol/l), a nonspecific inhibitor of guanylate cyclase, CNP (0.1 micromol/l)-induced inhibition of I(Ba) was partially blocked (n = 13, p < 0.05 ). However, when the cell was pretreated with zaprinast (0.1 micromol/l), an inhibitor of cyclic guanosine monophosphate (cGMP) sensitive phosphoesterase, the inhibitory effect of CNP on I(Ba) was significantly potentiated (n = 11, p < 0.05). KT5823 (1 micromol/l), a cGMP-dependent protein kinase (PKG) inhibitor, almost completely blocked CNP-induced inhibition of I(Ba). The results suggested that CNP can inhibit L-type calcium channel currents, and the inhibitory effect is mediated by pGC-cGMP-PKG-dependent signal pathway in gastric antral myocytes of guinea pigs.
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PMID:Inhibitory effect of C-type natriuretic peptide on L-type calcium channel currents in gastric antral myocytes of guinea pigs. 1735 30

Hairy/Enhancer of split (Hes) 6 is a basic helix-loop-helix protein that interacts with the transcriptional co-repressor, Groucho, and antagonizes the neural functions of the Notch pathway. More specifically, mouse Hes6 regulates cerebral corticogenesis by promoting neurogenesis and suppressing astrocyte differentiation. The molecular mechanisms underlying the anti-astrogenic function of Hes6 are poorly defined. Here we describe studies aimed at testing whether Hes6 inhibits astrocyte differentiation by antagonizing the transcription repression activity of Notch-activated Hes family members like Hes1. It is reported that Hes6 preferentially forms homodimers. Heterodimerization with Hes1 is antagonized in part by a conserved N-terminal patch of negatively charged residues. Mutation of this motif enhances heterodimerization with Hes1 and increases Hes6 ability to antagonize Hes1-mediated transcriptional repression. However, this mutation does not increase, but instead decreases, the anti-astrogenic activity of Hes6. It is shown further that Hes6 harbors a second conserved sequence, a C-terminal SPXXSP motif. This sequence is phosphorylated by the mitogen activated protein kinase pathway and its mutation disrupts the anti-astrogenic activity of Hes6 without affecting its ability to suppress Hes1. Together, these observations suggest that Hes6 homodimers regulate astrocyte differentiation through mechanisms that depend on the phosphorylation of Hes6 C-terminal domain but are independent of its ability to suppress Hes1-mediated transcriptional repression.
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PMID:Inhibition of cortical astrocyte differentiation by Hes6 requires amino- and carboxy-terminal motifs important for dimerization and phosphorylation. 1786 20

K(+) channels play indispensable roles in establishing the membrane potential and in regulating the contractile tone of arterial smooth muscle cells. There are four types of K(+) channels in arterial smooth muscle: voltage-dependent K(+) (K(V)), Ca(2+)-dependent K(+) (BK(Ca)), ATP-dependent K(+) (K(ATP)), and inward rectifier K(+) (Kir2) channels. Comparatively few physiological studies have focused on Kir2 channels because they are present only in certain small-diameter cerebral and submucosal arterioles and in coronary arterial smooth muscle. Here, we review the characteristics and regulation of Kir2 channels in vascular arterial smooth muscle. Current knowledge of the predominant Kir2 channel subtype is Kir2.1, not Kir2.2 and 2.3. Electrophysiological measurements to determine the current-voltage relationship in arterial smooth muscle revealed inward rectification with a single-channel conductance of 21 pS. Kir2 channels were found to influence the resting tone of cerebral and coronary arteries based on the fact that barium (Ba(2+)) induces the constriction of these arteries at resting tone. Kir2 channels are also highly responsive to vasoconstrictors and vasodilators. For example, the vasoconstrictors endothelin-1 and angiotensin II inhibit Kir2 channel function by activating protein kinase C (PKC), and the vasodilator adenosine stimulates Kir2 channel function by increasing the level of cAMP, which subsequently activates protein kinase A (PKA). Certain pathological conditions such as left ventricular hypertrophy are associated with a decrease in Kir2 channel expression. Although our understanding of the physiological role and regulation of Kir2 channels is incomplete, it is believed that Kir2 channels contribute to the control of vascular tone in small-diameter vessels via various intracellular signalling pathways that regulate cell membrane potential.
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PMID:Physiological role of inward rectifier K(+) channels in vascular smooth muscle cells. 1843 13

Glucagon-like peptide-2 (GLP-2) is a neuropeptide secreted from endocrine cells in the gut and neurons in the brain. GLP-2 stimulates intestinal crypt cell proliferation and mucosal blood flow while decreasing gastric emptying and gut motility. However, a GLP-2-mediated signaling network has not been fully established in primary cells. Since the GLP-2 receptor mRNA and protein were highly expressed in the mouse hippocampus, we further characterized that human (125)I-labeled GLP-2(1-33) specifically bound to cultured hippocampal neurons with K(d) = 0.48 nM, and GLP-2 acutely induced subcellular translocalization of the early gene c-Fos. Using the whole cell patch clamp, we recorded barium currents (I(Ba)) flowing through voltage-gated Ca(2+) channels (VGCC) in those neurons in the presence of GLP-2 with and without inhibitors. We showed that GLP-2 (20 nM) enhanced the whole cell I(Ba) mediated by L-type VGCC that was defined using an L-type Ca(2+) channel blocker (nifedipine, 10 microM). Moreover, GLP-2-potentiation of L-type VGCC was abolished in neurons pretreated with a PKA inhibitor (PKI(14-22), 1 microM). Finally, using a fluorescent nonmetabolized glucose analog (6-NBDG) tracing imaging, we showed that glucose was taken up directly by cultured neurons. GLP-2 increased 2-deoxy-d-[(3)H]glucose uptake that was dependent upon dosage, activation of PKA, and potentiation of L-type VGCC. We conclude that GLP-2 potentiates L-type VGCC activity through activating PKA signaling, partially stimulating glucose uptake by primary cultured hippocampal neurons. The potentiation of L-type VGCC may be physiologically relevant to GLP-2-induced neuroendocrine modulation of neurotransmitter release and hormone secretion.
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PMID:GLP-2 potentiates L-type Ca2+ channel activity associated with stimulated glucose uptake in hippocampal neurons. 1992 Feb 20


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