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 importance of second-messenger systems in controlling the excitability of neurones and other cells, through modulation of voltage- and calcium-dependent ionic conductances, has become increasingly clear. Cyclic AMP, acting via protein kinase A, has been identified as the second messenger for several neurotransmitters, and recent studies have suggested that activation of protein kinase C may have similar modulatory actions on neurones. Calcium and potassium currents have so far been shown to be the major ionic conductances modified by kinase activation. We now report that hippocampal pyramidal cells contain a previously undescribed voltage-dependent chloride current which is active at resting potential and is turned off either by membrane depolarization or by activation of protein kinase C by phorbol esters. We propose that this current may reside predominantly in the cell's dendritic membrane and thereby may regulate dendritic excitability.
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PMID:Phorbol esters block a voltage-sensitive chloride current in hippocampal pyramidal cells. 242 84

Recent studies have provided evidence for a role of protein phosphorylation in the regulation of the function of various potassium and calcium channels (for reviews, see refs 1, 2). As these ion channels have not yet been isolated and characterized, it has not been possible to determine whether phosphorylation of the ion channels themselves alters their properties or whether some indirect mechanism is involved. In contrast, the nicotinic acetylcholine receptor, a neurotransmitter-dependent ion channel, has been extensively characterized biochemically and has been shown to be directly phosphorylated. The phosphorylation of this receptor is catalysed by at least three different protein kinases (cyclic AMP-dependent protein kinase, protein kinase C and a tyrosine-specific protein kinase) on seven different phosphorylation sites. However, the functional significance of phosphorylation of the receptor has been unclear. We have now examined the functional effects of phosphorylation of the nicotinic acetylcholine receptor by cAMP-dependent protein kinase. We investigated the ion transport properties of the purified and reconstituted acetylcholine receptor before and after phosphorylation. We report here that phosphorylation of the nicotinic acetylcholine receptor on the gamma- and delta-subunits by cAMP-dependent protein kinase increases the rate of the rapid desensitization of the receptor, a process by which the receptor is inactivated in the presence of acetylcholine (ACh). These results provide the first direct evidence that phosphorylation of an ion channel protein modulates its function and suggest that phosphorylation of postsynaptic receptors in general may play an important role in synaptic plasticity.
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PMID:Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization. 242 85

Second messenger systems may modulate neuronal activity through protein phosphorylation. However, interactions between two major second messenger pathways, the cyclic AMP and phosphatidylinositol systems, are not well understood. The effects of activators of cyclic AMP-dependent protein kinase and protein kinase C on resting membrane properties, action potentials, and currents recorded from mouse dorsal root ganglion neurons and cerebral hemisphere neurons grown in primary dissociated cell culture were investigated. Neither forskolin (FOR) nor phorbol 12,13-dibutyrate (PDBu) altered resting membrane properties but both increased the duration of calcium-dependent action potentials in both central and peripheral neurons. By means of the single-electrode voltage clamp technique, FOR and PDBu were shown to decrease the same voltage-dependent potassium conductance. This suggests that two independent second messenger systems may affect the same potassium conductance.
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PMID:Forskolin and phorbol esters reduce the same potassium conductance of mouse neurons in culture. 243 63

The effects of agonists at mu and delta opioid receptors were compared by measuring membrane currents under voltage clamp from neurons of the rat nucleus locus coeruleus and guinea pig submucous plexus. In each tissue, the appropriate selective agonist (Tyr-D-Ala-Gly-MePhe-Gly-ol for mu receptors in locus coeruleus or Tyr-D-Pen-Gly-Phe-D-Pen for delta receptors in submucous plexus) increased the conductance of an inwardly rectifying potassium conductance and strongly hyperpolarized the membrane. The properties of the potassium conductance affected by the two opioids could not be distinguished. Experiments with intracellular application of guanosine 5'-[gamma-thio]triphosphate indicated that a guanine nucleotide-binding regulatory protein was involved in the coupling between opioid receptor and potassium channel, but there was no evidence for activation of either cAMP-dependent protein kinase or protein kinase C. It is noted that a number of vertebrate neurotransmitter receptors are coupled to potassium channels. The potassium conductance associated with these channels has properties similar to the conductance activated by mu and delta opioids; this family includes the following receptors: acetylcholine M2, norepinephrine alpha 2, dopamine D2, 5-hydroxytryptamine 5-HT1, adenosine A1, gamma-aminobutyric acid GABAB, and somatostatin. It is suggested that this conductance is a conserved neuronal effector coupled to one of the receptor types that mediates the effects of each of several major transmitters. The mu and delta opioid receptors appear to be unusual in that both utilize this same effector mechanism.
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PMID:Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. 244 52

A possible direct effect of guanine nucleotide binding (G) proteins on calcium channels was examined in membrane patches excised from guinea pig cardiac myocytes and bovine cardiac sarcolemmal vesicles incorporated into planar lipid bilayers. The guanosine triphosphate analog, GTP gamma S, prolonged the survival of excised calcium channels independently of the presence of adenosine 3',5'-monophosphate (cAMP), adenosine triphosphate, cAMP-activated protein kinase, and the protein kinase C activator tetradecanoyl phorbol acetate. A specific G protein, activated Gs, or its alpha subunit, purified from the plasma membranes of human erythrocytes, prolonged the survival of excised channels and stimulated the activity of incorporated channels. Thus, in addition to regulating calcium channels indirectly through activation of cytoplasmic kinases, G proteins can regulate calcium channels directly. Since they also directly regulate a subset of potassium channels, G proteins are now known to directly gate two classes of membrane ion channels.
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PMID:A G protein directly regulates mammalian cardiac calcium channels. 244 90

In taste chemoreception, cyclic adenosine monophosphate (cAMP) appears to be one of the intracellular messengers coupling reception of stimulus to the generation of the response. The recent finding that sweet agents cause a GTP-dependent generation of cAMP poses the question of how this cytosolic messenger acts at the membrane of taste receptor cells. We have shown that cAMP causes a substantial depolarization in these cells. Here we show with whole-cell recordings and inside-out membrane patches that the depolarization caused by cAMP is accounted for by the action of cAMP-dependent protein kinase, which inactivates potassium channels predominantly of 44 pS conductance. Thus, intracellular signalling of the gustatory cells differs from that of olfactory and photoreceptor cells, where cyclic nucleotides control unspecific channels by binding to them rather than by inducing their phosphorylation.
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PMID:Transduction in taste receptor cells requires cAMP-dependent protein kinase. 244 43

beta-Adrenergic stimulation of ventricular heart cells results in the enhancement of two important ion currents that regulate the plateau phase of the action potential: the delayed rectifier potassium channel current (IK) and L-type calcium channel current (ICa). The temperature dependence of beta-adrenergic modulation of these two currents was examined in patch-clamped guinea pig ventricular myocytes at various steps in the beta-receptor/cyclic AMP-dependent protein kinase pathway. External applications of isoproterenol and forskolin were used to activate the beta-receptor and the enzyme adenylate cyclase, respectively. Internal dialysis of cyclic 3',5'-adenosine monophosphate (cAMP) or the catalytic subunit of cAMP-dependent protein kinase (CS), as well as the external addition of 8-chlorphenylthio cAMP (CPT-cAMP) was applied to increase intracellular levels of cAMP and CS. Isoproterenol-mediated increases in IK, but not ICa, were found to be very temperature dependent over the range of 20-37 degrees C. At room temperature (20-22 degrees C) isoproterenol produced a large (threefold) enhancement of ICa but had no effect on IK. In contrast, at warmer temperatures (30-37 degrees C) both currents increased in the presence of this agonist and the kinetics of IK were slowed at -30 mV. A similar temperature sensitivity also existed after exposure to forskolin, CPT-cAMP, cAMP, and CS, suggesting that this temperature sensitivity of IK may arise at the channel protein level. Modulation of IK during each of these interventions was accompanied by a slowing in IK kinetics. Thus, regulation of cardiac potassium channels but not calcium channels involves a temperature-dependent step that occurs after activation of the catalytic subunit of cAMP-dependent protein kinase.
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PMID:Beta-adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents. 247 62

In heart cells, cyclic AMP-dependent protein kinase (PKA) regulates calcium- and potassium-ion current by phosphorylating the ion channels or closely associated regulatory proteins. We report here that isoprenaline induced large chloride-ion currents in voltage-clamped, internally-dialysed myocytes from guinea-pig ventricles. The Cl- current could be activated by intracellular dialysis with cAMP or the catalytic subunit of PKA, indicating regulation by phosphorylation. In approximately symmetrical solutions of high Cl- concentration, the macroscopic cardiac Cl- current showed little rectification, unlike the single-channel current in PKA-regulated Cl- channels of airway epithelial cells. But, like epithelial Cl- -channel currents, the cardiac Cl- current was sensitive to the distilbene,4,4'-dinitrostilbene-2,2'-disulphonic acid (DNDS). In the absence of kinase activation, cardiac sarcolemmal Cl- conductance was negligible. During beta-adrenergic stimulation of the heart, this novel Cl- conductance should accelerate action-potential repolarization and so protect impulse propagation in the face of the possibly arrhythmogenic increases in heart rate and in calcium entry into the cells.
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PMID:Chloride conductance regulated by cyclic AMP-dependent protein kinase in cardiac myocytes. 247 83

Exposure of the bag cell neurons of Aplysia to activators of protein kinase C, such as phorbol esters, enhances electrically evoked action potentials by increasing the voltage-dependent calcium current. We have hypothesized that this effect is mediated by the activation of protein kinase C (PKC). An important prediction of this hypothesis is that inhibitors of PKC should inhibit these phorbol ester-induced changes in bag cell neuronal excitability. We have now found that treatment of bag cell neurons with the protein kinase inhibitor 1-[5-isoquinolinesulfonyl]-2-methyl piperazine (H-7) inhibits the phorbol ester-induced enhancement of bag cell action potentials and prevents the enhancement of calcium current by phorbol esters. The height and width of electrically evoked action potentials in bag cell neurons can also be enhanced by cAMP analogs or agents that elevate cAMP. These agents do not influence the major voltage-dependent calcium current in the bag cell neurons but may act by modulating potassium currents and other voltage-dependent currents. We have found that microinjection of a protein inhibitor of cAMP-PK (PKA-I) into isolated bag cell neurons prevents and reverses the effect of the adenylate cyclase activator forskolin on action potentials of these cells. In contrast, H-7 does not inhibit the effects of forskolin on a variety of responses in these cells, including its effects on action potentials, granule movement, and 32P incorporation into phosphoproteins. This suggests that H-7 is selective for PKC relative to cAMP-PK in intact bag cell neurons.
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PMID:Protein kinase inhibitors selectively block phorbol ester- or forskolin-induced changes in excitability of Aplysia neurons. 253 89

Experiments were carried out in single ventricular cells of the guinea-pig heart. Isoproterenol, forskolin, intracellularly applied cyclic AMP and 3-isobutyl-1-methylxanthine increased the delayed rectifier potassium current (IK). The effect of isoproterenol was abolished by intracellularly applied guanosine 5'-O-(3-thio-triphosphate). These results indicate that isoproterenol stimulates beta-adrenoceptors to activate adenylate cyclase by mediation through the stimulatory GTP-binding protein, and causes an increase in intracellular cyclic AMP levels. Then IK is probably increased by phosphorylation of the IK-channel protein by cyclic AMP-dependent protein kinase.
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PMID:Mechanisms of beta-adrenoceptor mediated increase in delayed rectifier potassium current. 256 Dec 34


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