EC:2.7.11.13 - FACTA Search

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of protein tyrosine kinases (PTKs) on L-type calcium channel currents was studied in cultured rat and human retinal pigment epithelial cells. Barium currents through L-type channels were measured in the perforated patch-clamp technique and identified by using the L-type calcium channel opener Bay K8644 (10(-6) M). Application of the PTK blockers genistein (5 x 10(-6) M) or lavendustin A (5 x 10(-6) M) led to a decrease of L-type currents. The inactive genistein analog daidzein (10(-5) M) showed no effect on calcium channels. Intracellular application of pp60(c-src) (30 U/ml) via the patch-pipette during the conventional whole-cell configuration led to an increase of L-type currents. The protein kinase A and protein kinase G blocker H9 (10(-6) M) showed no effect on L-type currents; genistein reduced the current in the presence of H9. The protein kinase C (PKC) blocker chelerythrine (10(-5) M) reduced the L-type current; additional inhibition of PTK by lavendustin showed an additional reduction of currents. Intracellular application of myristoylated PKC substrate (5 x 10(-5) M) for PKC inhibition led to a fast rundown of L-type current amplitudes. Intracellularly applied myristoylated PKC substrate (10(-4) M) together with pp60(c-src) showed no effect on L-type current. Up-regulation of PKC by 10(-6) M phorbol-12-myristate-13-acetate (PMA) had no effect on the L-type current amplitude. However, genistein in cells pretreated with PMA led to an increase of the L-type currents. Intracellular application of pp60(c-src) in PMA-treated cells led to a reduction of L-type currents. We conclude that in the resting cell, PTK and PKC regulate L-type calcium channels in an additive manner. L-type channels appeared as a site of integration of PTK activation and of PKC-dependent pathways. The activity of PKC determines whether PTK decreases or increases L-type channel activity.
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PMID:Regulation of L-type calcium channels by protein tyrosine kinase and protein kinase C in cultured rat and human retinal pigment epithelial cells. 928 84

We investigated how the L-type calcium channel blockade (CCB) with nifedipine affects the cyclic AMP responses to noradrenaline or isoproterenol in cerebral cortical slices from rats receiving antidepressant treatments that induce (electroconvulsive shock, imipramine) or do not induce (amitriptyline) beta-downregulation. To assess the role of protein kinase C (PKC) in receptor crosstalk under CCB conditions, the cyclic AMP responses were tested also in the presence of a PKC activator, TPA. CCB alone induced no changes, but modulated the action of those antidepressants that down regulate the beta-adrenergic system. Chronic ECS and imipramine treatments were differently affected. ECS, under conditions of CCB, down regulated the response to isoproterenol in the presence of TPA, while imipramine ceased to block the TPA-potentiation of cyclic AMP responses. Thus, CCB affects the processes related to the antidepressant-induced changes on the crosstalk between alpha1- and beta-adrenergic receptors, depending on the specific properties of the antidepressant.
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PMID:Does Ca2+ channel blockade modulate the antidepressant-induced changes in mechanisms of adrenergic transduction? 929 84

Calcium ionophore A23187 or phenylephrine injected i.p. in doses of 0.05-0 .25 mg kg-1 and 0.1-1 mg kg-1, respectively, induced translocation of protein kinase C (PKC) from the cytosol to the membrane fraction of the rat frontal cortex and hippocampus. The action of A23187 was blocked in a dose-dependent manner by nifedipine and verapamil. The phenylephrine induced translocation of PKC was blocked by prazosin and in a dose-dependent manner by nifedipine and verapamil. In contrast, pre-treatment with a small, ineffective by itself, dose of A23187 (0.02 mg kg-1) potentiated the alpha1-adrenoceptor induced translocation of PKC. Thus, it seems that the influx of calcium ions through an L-type calcium channel is probably necessary for a full alpha1-adrenoceptor mediated activation and translocation of PKC.
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PMID:The cooperation between the influx of extracellular calcium and alpha1-adrenoceptor-induced translocation of protein kinase C. 936 66

It is generally accepted that ATP is costored and coreleased with noradrenaline from the sympathetic nerve terminals. The pacemaker region of the mammalian heart is highly innervated with the sympathetic nervous system. It is possible, therefore, that ATP released from nerve terminals can act on pacemaker cells and modulate heart beat activity. However, the physiological role(s) of extracellular ATP in mammalian heart beat has been little evaluated, even though the effect of extracellular ATP observed in in vivo studies has been attributed to the formation of adenosine, the catabolic product of ATP, which is a cardiodepressant. The present study investigated the effect of extracellular ATP on L-type calcium channel currents of guinea-pig single sinoatrial nodal cells, by using the whole cell patch clamp technique. Application of extracellular ATP caused a concentration-dependent and reversible inhibition of calcium channel currents with a 50% inhibitory concentration of 100 microM. The presence of the P2-purinoceptor antagonist suramin (1, 10 and 100 microM), reactive blue 2 (1 and 10 microM) and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 50 and 100 microM) or the adenosine receptor antagonists 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX, 0.1 microM) and 8-phenyltheophylline (10 microM) failed to affect the inhibitory action of extracellular ATP on calcium channel currents. The relative rank order of potency of different nucleotides and nucleosides, at a concentration of 100 microM, on the inhibition of calcium channel currents was as follows: ATP = alpha, beta-methylene-ATP >> 2-methylthioATP > or = adenosine 5'-O-(3-thiotriphosphate) >> UTP = ADP > AMP > or = adenosine. Dialysis, by way of the patch pipette, of the cell interior with specific protein kinase C inhibitor staurosporine (70 nM) or calphostin C (500 nM) abolished extracellular ATP-induced inhibition of calcium channel currents. Therefore, extracellular ATP-mediated inhibition of calcium channel currents in guinea-pig single sinoatrial nodal cells involves activation of protein kinase C.
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PMID:Inhibition by extracellular ATP of L-type calcium channel currents in guinea-pig single sinoatrial nodal cells: involvement of protein kinase C. 944 3

In rat cortical primary cultures, group II- and III-metabotropic glutamate receptor-selective agonists concentration-dependently reduced KCl-induced [3H]GABA release, with IC50 values of 11 nM for LY354740, 80 nM for L(+)-2-amino-4-phosphonobutyric acid (L-AP4), 180 nM for DCG-IV, and 330 nM for L-SOP. The group II antagonists, LY341495 and EGLU, reversed the effect of LY354740, and the group III antagonist MTPG reversed the effect of L-AP4. In the presence of omega-conotoxin GVIA, LY354740 inhibited the remaining [3H]GABA release, whereas L-AP4 was inactive. In contrast, in the presence of nifedipine, L-AP4 inhibited the remaining [3H]GABA release, but LY354740 was no longer active. The PKA inhibitor, H89, blocked the effects of both L-AP4 and LY354740, whereas the PKC inhibitor Ro 31-8220 blocked only the effect of LY354740. Both Ro 31-8220 and H89 reduced the [3H]GABA release to 60% of control. In whole-cell, voltage-clamp experiments, LY354740 and L-AP4 inhibited voltage-gated calcium channel currents with IC50 values of 28 nM and 22 microM, respectively. The results suggest that, in these cells, KCl-induced [3H]GABA release is modulated by two different mechanisms, one involving group II receptors and a direct control of the Ca2+ channel activity, and the other mediated by group III receptors and possibly involving a regulation located downstream of the Ca2+ channel activation.
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PMID:Multiple pathways for regulation of the KCl-induced [3H]-GABA release by metabotropic glutamate receptors, in primary rat cortical cultures. 951 53

The regulation of LH and FSH subunit gene expression is under the control of GnRH. Physiological changes in the frequency of pulsatile GnRH release from the hypothalamus result in differential stimulation of alpha-, LHbeta-, and FSHbeta-gene expression. Previous studies indicate that the GnRH receptor couples to G proteins of the G(q/11) family, with phosphoinositide turnover and its resultant increase in intracellular calcium concentration and protein kinase C (PKC) activation, to stimulate secretion of LH and FSH. However, the molecular mechanisms by which GnRH mediates its transcriptional effects remain largely unknown. We used GH3 cells, constitutively expressing the rat GnRH receptor (GGH(3)-1' cells) and transiently transfected with a luciferase reporter gene controlled by either the alpha, LHbeta, or FSHbeta gene regulatory region (alphaLUC, LHbetaLUC, and FSHbetaLUC, respectively), to examine the roles of several signal transduction pathways in the GnRH-mediated stimulation of gonadotropin subunit gene expression. Activation of PKC by phorbol, 12-myristate, 13-acetate resulted in an increase in the luciferase activity of all three gonadotropin subunit gene reporter constructs. Phorbol, 12-myristate, 13-acetate had a greater stimulatory effect, relative to the maximal stimulation with GnRH, for the beta-subunit genes than for the alpha-subunit gene. Depletion of PKC, or inhibition of PKC by GF109203X, demonstrated that PKC-dependent pathways play a larger role in the GnRH-mediated transcriptional control of the LHbeta- and FSHbeta-genes than the alpha-subunit gene. In contrast, an L-type calcium channel agonist, Bay K 8644, was able to stimulate alphaLUC but not LHbetaLUC or FSHbetaLUC. Nimodipine, an L-type calcium channel antagonist, had a larger inhibitory effect on the GnRH response of alphaLUC, relative to LHbetaLUC or FSHbetaLUC. We conclude from these results that the differential regulation of gonadotropin subunit gene expression by GnRH is caused, in part, by differential use of signal transduction pathways, activated upon GnRH binding.
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PMID:Differential use of signal transduction pathways in the gonadotropin-releasing hormone-mediated regulation of gonadotropin subunit gene expression. 952 69

Earlier autoradiographic studies from our laboratory detected vasopressin recognition sites in the mammalian cerebral cortex [R.E. Brinton, K.W. Gee, J.K. Wamsley, T.P. Davis, H.I. Yamamura, Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography, Proc. Natl. Acad. Sci. U. S.A., 81 (1984) 7248-7252; C. Chen, R.D. Brinton, T.J. Shors, R.F. Thompson, Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus, Hippocampus, 3 (1993) 193-204]. More recently, we have detected mRNA for the V1a vasopressin receptors (V1aRs) in cultured cortical neurons [R.S. Yamazaki, Q. Chen, S.S. Schreiber, R.D. Brinton, V1a Vasopressin receptor mRNA expression in cultured neurons, astroglia, and oligodendroglia of rat cerebral cortex, Mol. Brain Res., 45 (1996) 138-140]. To determine whether these recognition sites are functional receptors, we have pursued the signal transduction mechanism associated with the V1a vasopressin receptor in enriched cultures of cortical neurons. Results of these studies demonstrate that exposure of cortical neurons to the selective V1 vasopressin receptor agonist, [Phe2,Orn8]-vasotocin, (V1 agonist) induced a significant accumulation of [3H]inositol-1-phosphate ([3H]IP1). V1 agonist-induced accumulation of [3H]IP1 was concentration dependent and exhibited a linear dose response curve. Time course analysis of V1 agonist-induced accumulation of [3H]IP1 revealed a significant increase by 20 min which then decreased gradually over the remaining 60 min observation period. V1 agonist-induced accumulation of [3H]IP1 was blocked by a selective V1a vasopressin receptor antagonist, (Phenylac1, D-Tyr(Me)2, Arg6,8, Lys-NH29)-vasopressin. Results of calcium fluorometry studies indicated that V1 agonist exposure induced a marked and sustained rise in intracellular calcium which was abolished in the absence of extracellular calcium. The loss of the rise in intracellular calcium was not due to a failure to induce PIP2 hydrolysis since activation of the phosphatidylinositol pathway occurred in the absence of extracellular calcium. V1 agonist activation of calcium influx was then investigated. V1 agonist-induced 45Ca2+ uptake was concentration dependent with a biphasic time course at 250 nM. Preincubation with the L-type calcium channel blocker, nifedipine, blocked V1 agonist-induced calcium influx suggesting V1 agonist-induced L-type calcium channel activation in cortical neurons. Furthermore, V1 agonist-induced calcium influx was blocked by both bisindolyleimide I (PKC inhibitor) and U-73122 (PLC inhibitor) suggesting a modulation of V1 agonist-induced L-type calcium channel activation by downstream components of the phosphatidylinositol signaling pathway such as protein kinase C. These results indicate that in cultured cortical neurons, V1a vasopressin receptor activation leads to induction of the phosphatidylinositol signaling pathway, influx of extracellular calcium via L-type calcium channel activation, and a rise in intracellular calcium which is dependent on V1a receptor activated influx of extracellular calcium. These data are the first to demonstrate an effector mechanism for the V1 vasopressin receptor in the cerebral cortex and provide a potential biochemical mechanism that may underlie vasopressin enhancement of memory function.
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PMID:Vasopressin-induced calcium signaling in cultured cortical neurons. 963 Jun 55

Cell differentiation of PC12 cells was electrically induced to grow neurites in the absence of nerve growth factor (NGF) on the electrode surface, of which potential was modulated by a rectangular wave of potential. The electric stimulation induced the c-fos expression which is essential for cell differentiation. Non-specific calcium channel blocker, lanthanum ion, inhibited the electrically induced differentiation, while NGF-induced differentiation was not suppressed. An L-type calcium channel blocker, nifedipine, also inhibited the electrically induced calcium influx and c-fos expression. Moreover, a stretch-activated (SA) channel blocker, gadolinium ion, inhibited the electrically stimulated differentiation by blocking the calcium influx, but gave no prominent effects on the potassium ion-induced differentiation. Chelerythrine, a specific protein kinase C (PKC) inhibitor, almost inhibited the cell differentiation by the electric stimulation but not by the NGF treatment. These results indicate that the alternative potential may stimulate cell differentiation through a PKC cascade.
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PMID:Gene expression in the electrically stimulated differentiation of PC12 cells. 976 82

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed by one-third of adult rat lumbar dorsal root ganglion (DRG) neurons, many of which mediate pain sensation or cause vasodilation. The factors that regulate the developmental expression of CGRP are poorly understood. Embryonic DRG neurons initially lack CGRP. When these neurons were stimulated in culture by serum or persistent 50 mM KCl application, the same percentage of CGRP-immunoreactive (CGRP-IR) neurons developed in vitro as was seen in the adult DRG in vivo. The addition of the L-type calcium channel blockers, 5 microM nifedipine or 10 microM verapamil, dramatically decreased the proportion of CGRP-IR neurons that developed, although the N-type calcium channel blocker, 2.5 microM omega-conotoxin, was less effective. By contrast, the sodium channel blocker 1 microM tetrodotoxin had no effect on CGRP expression after depolarization. Fura-2 ratiometric imaging demonstrated that mean intracellular free calcium levels increased from 70 to 135 nM with chronic depolarization, and the addition of nifedipine inhibited that increase. Only a subpopulation of neurons had elevated calcium concentrations during chronic depolarization, and they were correlated with CGRP expression. Key signal transduction pathways were tested pharmacologically for their role in CGRP expression after depolarization; the addition of the CaM kinase inhibitor KN-62 reduced the proportion of CGRP-IR neurons to basal levels. By contrast, protein kinase A and protein kinase C were not implicated in the depolarization-induced CGRP increases. These data suggest that depolarization and the subsequent Ca2+-based signal transduction mechanisms play important roles in the de novo expression of CGRP by specific embryonic DRG neurons.
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PMID:Depolarization stimulates initial calcitonin gene-related peptide expression by embryonic sensory neurons in vitro. 980 68

Glutamate is the primary excitatory transmitter in the suprachiasmatic nucleus (SCN). Ionotropic glutamate receptors (iGluRs) mediate transduction of light information from the retina to the SCN, an important circadian clock phase shifting pathway. Metabotropic glutamate receptors (mGluRs) may play a significant modulatory role. mGluR modulation of SCN responses to glutamate was investigated with fura-2 calcium imaging in SCN explant cultures. SCN neurons showed reproducible calcium responses to glutamate, kainate, and N-methyl-D-aspartate (NMDA). Although the type I/II mGluR agonists L-CCG-I and t-ACPD did not evoke calcium responses, they did inhibit kainate- and NMDA-evoked calcium rises. This interaction was insensitive to pertussis toxin. Protein kinase A (PKA) activation by 8-bromo-cAMP significantly reduced iGluR inhibition by mGluR agonists. The inhibitory effect of mGluRs was enhanced by activating protein kinase C (PKC) and significantly reduced in the presence of the PKC inhibitor H7. Previous reports show that L-type calcium channels can be modulated by PKC and PKA. In SCN cells, about one-half of the calcium rise evoked by kainate or NMDA was blocked by the L-type calcium channel antagonist nimodipine. Calcium rises evoked by K+ were used to test whether mGluR inhibition of iGluR calcium rises involved calcium channel modulation. These calcium rises were primarily attributable to activation of voltage-activated calcium channels. PKC activation inhibited K+-evoked calcium rises, but PKC inhibition did not affect L-CCG-I inhibition of these rises. In contrast, 8Br-cAMP had no effect alone but blocked L-CCG-I inhibition. Taken together, these results suggest that activation of mGluRs, likely type II, modulates glutamate-evoked calcium responses in SCN neurons. mGluR inhibition of iGluR calcium rises can be differentially influenced by PKC or PKA activation. Regulation of glutamate-mediated calcium influx could occur at L-type calcium channels, K+ channels, or at GluRs. It is proposed that mGluRs may be important regulators of glutamate responsivity in the circadian system.
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PMID:Metabotropic glutamate receptor modulation of glutamate responses in the suprachiasmatic nucleus. 1008 57

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