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)

Microtubules are present at postsynaptic densities in brain and are proposed to be involved in anchoring neurotransmitter receptor clusters at postsynaptic membranes. However, the influence of microtubules on gamma-aminobutyric acidA (GABAA) receptors has not been studied. Microtubule-affecting agents were tested for their actions on GABAA receptor function, by measuring muscimol-stimulated chloride uptake into cerebral cortical microsacs and proteoliposomes and GABA-mediated currents in Xenopus laevis oocytes expressing GABAA receptors. Colchicine, nocodazole, vinblastine, and taxol inhibited muscimol-stimulated chloride uptake. beta- and gamma-lumicolchicine did not inhibit GABAA ergic function. Colchicine decreased the potency of muscimol, a GABA agonist, to stimulate chloride uptake without affecting the specific binding of [3H]flunitrazepam or t-[35S]butylbicyclophosphorothionate to the GABAA receptor, or the allosteric modulation of binding of these ligands by muscimol. The function of purified GABAA receptors reconstituted in proteoliposomes, a preparation not containing microtubule components, was not affected by colchicine. In contrast to the results seen in human monocytes by other investigators, we found that colchicine decreased, rather than increased, protein kinase A activity in cortical microsacs. Thus, protein kinase A modulation of the GABAA receptor is not a likely mechanism for the actions of colchicine. We propose that microtubule-depolymerizing agents inhibit GABAA ergic function by disrupting the interaction of GABAA receptors with microtubules.
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PMID:Gamma-aminobutyric acidA receptor function is inhibited by microtubule depolymerization. 791 71

In the medium-sized spiny neurons of the striatonigral pathway, a cascade of events involving the activation of dopamine D1 receptors, an increase in cyclic AMP, and activation of cyclic AMP-dependent protein kinase causes the phosphorylation of DARPP-32 on Thr34, converting DARPP-32 into a powerful inhibitor of protein phosphatase-1. In the present study, the incubation of striatal or substantia nigra slices with GABA also increased the phosphorylation of DARPP-32 on Thr34. GABA did not significantly increase cyclic AMP levels in slices. The phosphorylation of DARPP-32 by GABA was blocked in both brain regions by pretreatment of slices with the GABAA receptor antagonist, bicuculline, but not with the GABAB receptor antagonist, phaclofen. Moreover, the threonine phosphorylation of DARPP-32 produced by maximally effective doses of either forskolin (in striatum) or L-3,4-dihydroxyphenylalanine (in substantia nigra) was increased further by GABA. The data are consistent with a model in which GABA increases the phosphorylation state of DARPP-32 by inhibiting dephosphorylation of the protein by the calcium/calmodulin-dependent protein phosphatase, calcineurin.
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PMID:Phosphorylation of DARPP-32 is regulated by GABA in rat striatum and substantia nigra. 793 32

We have examined the effects of ciliary neurotrophic factor (CNTF) on the development of rat Purkinje cells in vitro. Cerebellar cells, derived from embryonic day 16 rat fetuses, were found to respond rapidly to CNTF treatment by induction of c-Fos protein, such that 40% of the cells were immunopositive after 60 min. Treatment with low doses of CNTF (10-100 pg/ml) for 8 days resulted in an approximately 1.6-fold increase in the number of Purkinje cells, identified by immunohistochemical staining for calbindin. Immunohistochemical staining for other Purkinje cell markers--cyclic-GMP-dependent protein kinase and the low-affinity nerve growth factor receptor--verified increased Purkinje cell survival following CNTF treatment. In addition, CNTF increased specific high-affinity GABA uptake by 45%, and the number of GABAergic neurons by 70%. A maximal increase in the number of Purkinje cells and GABA-uptake was only achieved if CNTF was added within 48 h of plating the cells, further suggesting that CNTF enhances Purkinje cell survival in vitro. These results taken together strongly support a direct effect of CNTF in promoting the survival of Purkinje cells and possibly other GABAergic cerebellar neurons.
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PMID:Ciliary neurotrophic factor enhances the survival of Purkinje cells in vitro. 795 72

The gamma-aminobutyric acid type A (GABAA) receptor is the predominant Cl(-)-channel protein mediating inhibition in the retina and elsewhere in the mammalian brain. We have observed a time-dependent increase of GABA-induced whole-cell currents when dopamine was applied externally to rat retinal amacrine cells. After 20 min, the peak current was increased to 208% +/- 10% of its initial value. A comparable effect was observed with the dopamine D1 receptor agonist (+)-1-phenyl-2,3,4,5-tetrahydro(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) but not with the D2 agonist bromocryptine. The action of dopamine involved phosphorylation of GABAA receptors by protein kinase A, as evident from intracellular application of protein kinase A, cAMP, and forskolin. Both guanosine 5'-[gamma-thio]triphosphate and cholera toxin augmented the GABA response, indicating a role for the guanosine 5'-triphosphate-binding protein Gs in the transduction cascade. Phosphorylation of GABAA receptors shifted the half-maximally effective GABA concentration from 71 microM to 47 microM without affecting the maximal response amplitude. The elevated binding affinity for GABA was caused by an increase of the open probability of the channels from 0.09 to 0.33 (2 microM GABA); conductance and mean open time did not change. Several other receptor agonists such as adenosine, histamine, somatostatin, enkephalin, and vasoactive intestinal peptide were found to couple to the same intracellular phosphorylation pathway. Since some of these cotransmitters colocalize with GABA in amacrine cells, they may fine-tune GABAergic inhibition in the retina.
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PMID:Facilitation of GABAergic signaling in the retina by receptors stimulating adenylate cyclase. 797 79

gamma-Aminobutyric acid type A receptor subunits (GABAA) can be divided into five classes, alpha, beta, gamma, delta, and rho, based on sequence homology. We have used purified fusion proteins of the major intracellular domain of GABAA receptor subunits produced in Escherichia coli to examine the phosphorylation of these subunits by cGMP-dependent protein kinase (PKG) and multifunctional calcium/calmodulin-dependent protein kinase (CAM KII). Both PKG and CAM KII phosphorylated a purified beta 1 subunit fusion. Both of these kinases phosphorylated serine 409 within the beta 1 subunit; in addition, CAM KII also phosphorylated serine 384 as determined by site-specific mutagenesis. Fusion proteins of the major intracellular domains of the gamma 2S and gamma 2L subunits were produced. These proteins differ by 8 amino acids (LLRMFSFK). Both the gamma 2L and gamma 2S fusion proteins were excellent substrates of CAM KII. However, the gamma 2L fusion protein was phosphorylated to higher stoichiometry due to the phosphorylation of serine 343 within this 8-amino acid insertion. Both the gamma 2L and gamma 2S subunits were phosphorylated on common residues by CAM KII identified as serine 348 and threonine 350. These results identify specific sites of phosphorylation for CAM KII and PKG within GABAA receptor subunits, suggesting a role for these two kinases in modulating GABAA receptor function in vivo.
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PMID:Differential phosphorylation of intracellular domains of gamma-aminobutyric acid type A receptor subunits by calcium/calmodulin type 2-dependent protein kinase and cGMP-dependent protein kinase. 802 73

Intact bovine adrenal medullary chromaffin cells were preincubated with 32PO4, and the multiple-site phosphorylation of tyrosine hydroxylase (TH) was studied. Up to eight 32P-labeled peptides were produced by tryptic hydrolysis of TH; however, all of the tryptic phosphopeptides were derived from four phosphorylation sites--Ser8, Ser19, Ser31 and Ser40. In situ regulation of 32P incorporation into the latter three sites was demonstrated with a diverse set of pharmacological agents. 32P incorporation into Ser19 was preferentially increased by brief exposures to depolarizing secretagogues. Longer treatments also increased Ser31 and Ser40 phosphorylation. Nicotine, muscarine and vasoactive intestinal polypeptide--reflecting cholinergic and non-cholinergic components of sympatho-adrenal transmission--each produced different patterns of multiple-site phosphorylation of TH. Nicotine, bradykinin and histamine increased 32P incorporation at each of the three sites whereas muscarine, angiotensin II, endothelin III, prostaglandin E1, GABA and ATP selectively increased Ser31 phosphorylation. Nerve growth factor did not influence TH phosphorylation in chromaffin cells from adult adrenal glands but selectively increased Ser31 phosphorylation in chromaffin cells isolated from calf adrenal glands. 32P incorporation into Ser40 was selectively increased by forskolin and other cAMP-acting agents whereas vasoactive intestinal polypeptide increased Ser31 and Ser40 phosphorylation. Thus, the phosphorylation of TH in bovine chromaffin cells appears to be regulated at three sites by three separate intracellular signaling pathways--Ser19 via Ca2+/calmodulin-dependent protein kinase II; Ser31 via ERK (MAP2 kinases); and Ser40 via cAMP-dependent protein kinase. These signaling pathways, as well as the extracellular signals that were effective in stimulating them, are similar to those previously described for TH in rat pheochromocytoma cells. However, several of the pharmacological agents produced different patterns of multiple-site TH phosphorylation in the bovine chromaffin cells. These differences between tissues could be accounted for by differences in the coupling/access between the extracellular signal transduction systems and the intracellular signaling pathways as opposed to differences in the intracellular signaling pathways per se.
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PMID:Multiple signaling pathways in bovine chromaffin cells regulate tyrosine hydroxylase phosphorylation at Ser19, Ser31, and Ser40. 809 28

The environmental signals which regulate the development of central noradrenergic neurons are largely unknown. The aim of the present study was to search for factors affecting the development of these cells. Dissociated cultures of embryonic dorsal brainstem tissue, containing the nucleus locus coeruleus (LC), were established; norepinephrine (NE) and GABA uptake were assessed, and noradrenergic versus total neurons were identified and counted following immunocytochemical staining with tyrosine hydroxylase (TH) and neuron specific enolase (NSE) antibodies, respectively. Application of dibutyryl cAMP (dbcAMP), other cAMP analogs, or forskolin, to LC cultures resulted in a significant increase in NE uptake which was associated with up to a 4-fold increase in the number of TH immunoreactive cells (TH+). dbcAMP treatment caused an increase in the number of TH+ cells in LC cultures by enhancing their survival and/or by upregulating their phenotypic differentiation. A possible effect of dbcAMP on cell proliferation and transformation of non-noradrenergic cells to noradrenergic TH+ cells were examined and suggested not to underlie this effect of cAMP. Glial cells may mediate the effect of cAMP on noradrenergic neurons. Calcium was not involved in the trophic activity of dbcAMP, which was probably mediated by protein phosphorylation via cAMP dependent protein kinase. Insulin (25 micrograms/ml) was found to increase the number of TH+ cells by 73%. The beta-adrenergic agonist isoproterenol also increased the number of TH+ cells by 53%. We propose a neurotrophic role for NE during development of central noradrenergic neurons.
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PMID:Neurotrophic effects of cAMP generating systems on central noradrenergic neurons. 810 14

The effect of calcium-phospholipid-dependent protein kinase (PKC) on GABAA receptor function was examined in Xenopus oocytes expressing recombinant human GABAA receptor using two-electrode voltage-clamp measurements. Phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC, inhibited GABA-gated chloride currents by approximately 72% in oocytes expressing alpha 1 beta 1 gamma 2L subunit cDNAs. Phorbol 12-monomyristate (PMM), a negative control analogue of PMA, did not alter GABAA receptor responses. To investigate whether activation of PKC could alter the modulatory responses of the receptor complex the effect of PMA on benzodiazepine and barbiturate potentiation of GABA responses was assessed. In oocytes expressing alpha 1 beta 1 gamma 2L subunit cDNAs, diazepam (300 nM) potentiated GABA responses by approximately 160%. Following PMA (5-25 nM) treatment, diazepam potentiation was significantly increased to 333%. No effect of the inactive phorbol ester PMM (25 nM) was observed on diazepam potentiation of GABA responses. PMA enhancement of diazepam potentiation of GABA responses was also observed in oocytes expressing alpha 1 beta 1 gamma 2S subunit cDNAs, indicating that the unique PKC site present in the gamma 2L subunit is not required for observing the PMA effect. PMA (5-25 nM) also enhanced pentobarbital potentiation of GABA responses. In oocytes expressing alpha 1 beta 1 gamma 2L subunit cDNAs, pentobarbital (25 microM) potentiated GABA receptor responses by approximately 97%. Following treatment with PMA (5-25 nM), pentobarbital potentiation of GABA responses increased to approximately 156%. The present results suggest that protein phosphorylation may alter the coupling between the allosteric modulatory sites within the GABAA receptor complex.
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PMID:Activation of calcium-phospholipid-dependent protein kinase enhances benzodiazepine and barbiturate potentiation of the GABAA receptor. 838 29

The gamma 2 subunit of the GABA receptor (GABAA-R) is alternatively spliced. The long variant (gamma 2L) contains eight additional amino acids that possess a consensus sequence site for protein phosphorylation. Previous studies have demonstrated that a peptide or fusion protein containing these eight amino acids is a substrate for protein kinase C (PKC), but not cyclic AMP-dependent protein kinase A (PKA)-stimulated phosphorylation. We have examined the ability of PKA, PKC, and Ca2+/calmodulin-dependent protein kinase (CAM kinase II) to phosphorylate a synthetic peptide corresponding to residues 336-351 of the intracellular loop of the gamma 2L subunit and inclusive of the alternatively spliced phosphorylation consensus sequence site. PKC and CAM kinase II produced significant phosphorylation of this peptide, but PKA was ineffective. The Km values for PKC- and CAM kinase II-stimulated phosphorylation of this peptide were 102 and 35 microM, respectively. Maximal velocities of 678 and 278 nmol of phosphate/min/mg were achieved by PKC and CAM kinase II, respectively. The phosphorylation site in the eight-amino-acid insert of the gamma 2L subunit has been shown to be necessary for ethanol potentiation of the GABAA-R. Thus, our results suggest that PKC, CAM kinase II, or both may play a role in the effects of ethanol on GABAergic function.
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PMID:Ca2+/calmodulin-dependent protein kinase II and protein kinase C phosphorylate a synthetic peptide corresponding to a sequence that is specific for the gamma 2L subunit of the GABAA receptor. 839 May 66

We have previously demonstrated that the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1 aminocyclopentane-1,3-dicarboxylate (ACPD) presynaptically inhibits evoked glutamatergic EPSCs and GABAergic IPSCs in patch clamped rat nucleus tractus solitarius (NTS) neurons recorded in this slices. The present study investigated the pharmacology of the presynaptic mGluRs, the the voltage dependent Ca2+ channel (VDCC) subtypes supporting neurotransmitter release, and possible interactions between the two. Monosynaptic EPSCs or IPSCs were evoked by electrical stimulation in the region of the tractus solitarius (TS). The effects of the mGluR agonists ACPD, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I) and L-2-amino-4-phosphonobutyrate (AP4) were examined upon EPSCs. The effects of the above compounds and quisqualate (QUIS) were examined upon IPSCs. L-CCG-I proved the most potent inhibitor of EPSCs and IPSCs. The VDCC blockers omega-AGA-IVA (AGA), omega-conotoxin GVIA (GVIA), omega-conotoxin MVIIC (MVIIC) and nimodipine (NIM) were assessed for their ability to inhibit monosynaptic EPSCs and IPSCs. EPSCs were inhibited by GVIA >> AGA > or = MVIIC. IPSCs were inhibited by AGA > or = MVIIC >> GVIA. NIM was without effect on the EPSC or IPSC. The potency of mGluR inhibition of evoked synaptic transmission was assessed in the absence and following treatment with VDCC blockers. mGluR agonists blocked a greater percentage of the EPSC or IPSC following treatment with GVIA, but not the other VDCC antagonists, than under control conditions. We have previously demonstrated that the postsynaptic inhibitory effects of mGluR activation upon GABAA mediated currents can be mimicked by cyclic guanosine monophosphate (cGMP) analogs. The cGMP-dependent protein kinase (PKG) inhibitors H8 and Rp-8-4-chlorophenylthio-guanosine-3',5'-cyclic monophosphorothioate (Rp-cG) blocked mGluR inhibition of GABAA mediated currents without blocking the ability of mGluR agonists to inhibit the IPSC. The effect of L-CCGI was enhanced following treatment with GVIA in the presence of Rp-cG, confirming a presynaptic locus of mGluR mediated inhibition of the IPSC. In contrast, cGMP analogues potentiate postsynaptic responses to glutamate agonists but depress the EPSC. As with the mGluR agonists, the inhibition of the EPSC by cGMP was potentiated following treatment with GVIA. These results suggest that presynaptic mGluR reduce both glutamate release from afferent fibers and GABA release from inhibitory interneurons following electrical stimulation in the region of the TS. Although different VDCCs support the majority of glutamate and GABA release and mGluR effects on release appear to utilize differing intracellular pathways, presynaptic GVIA-insensitive VDCCs are favorably targeted for inhibition by mGluR agonists.
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PMID:Presynaptic metabotropic glutamate receptors modulate omega-conotoxin-GVIA-insensitive calcium channels in the rat medulla. 853 76


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