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)

Specification of neurotransmitter phenotype is critical for neural circuit development and is influenced by intrinsic and extrinsic factors. Recent findings in rat hypothalamus in vitro suggest the role of neurotransmitter glutamate in the regulation of cholinergic phenotype. Here we extended our previous studies on the mechanisms of glutamate-dependent regulation of cholinergic phenotypic properties in hypothalamic neurons. Using immunocytochemistry, electrophysiology, and calcium imaging, we demonstrate that hypothalamic expression of choline acetyltransferase (the cholinergic marker) and responsiveness of neurons to acetylcholine (ACh) receptor agonists increase during chronic administration of an N-methyl-D-aspartate receptor (NMDAR) blocker, MK-801, in developing rats in vivo and genetic and pharmacological inactivation of NMDARs in mouse and rat developing neuronal cultures. In hypothalamic cultures, an inactivation of NMDA receptors also induces ACh-dependent synaptic activity, as do inactivations of PKA, ERK/MAPK, CREB, and NF-kappaB, which are known to be regulated by NMDA receptors. Interestingly, the increase in cholinergic properties in developing neurons that is induced by NMDAR blockade is prevented by the blockade of ACh receptors, suggesting that function of ACh receptor is required for the cholinergic up-regulation. Using dual recording of monosynaptic excitatory postsynaptic currents, we further demonstrate that chronic inactivation of ionotropic glutamate receptors induces the cholinergic phenotype in a subset of glutamatergic neurons. The phenotypic switch is partial as ACh and glutamate are coreleased. The results suggest that developing neurons may not only coexpress multiple transmitter phenotypes, but can also change the phenotypes following changes in signaling in neuronal circuits.
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PMID:Regulation of cholinergic phenotype in developing neurons. 1832 6

Glycine is the lone fast neurotransmitter for which a metabotropic pathway has not been identified. In retina, we found a strychnine-insensitive glycine response in bipolar and ganglion cells. This glycine response reduced high voltage-activated calcium current. It was G-protein mediated and protein kinase A dependent. The EC(50) of the metabotropic glycine response is 3 mum, an order of magnitude lower than the ionotropic glycine receptor in the same retina. The bipolar cell glutamatergic input to ganglion cells was suppressed by metabotropic glycine action. The synaptic output of about two-thirds of bipolar cells and calcium current in two-thirds of ganglion cells are sensitive to the action of glycine at metabotropic receptors, suggesting this signal regulates specific synaptic pathways in proximal retina. This study resolves the curious absence of a metabotropic glycine pathway in the nervous system and reveals that the major fast inhibitory neurotransmitters, GABA and glycine, both activate G-protein-coupled pathways as well.
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PMID:Synaptic inhibition by glycine acting at a metabotropic receptor in tiger salamander retina. 1844 Sep 92

Protein phosphorylation is an important mechanism for the post-translational modulation of ionotropic glutamate receptors. In this study, we investigated the regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit phosphorylation by the stimulation of group I metabotropic glutamate receptors (mGluRs) in the rat dorsal striatum in vivo. Stimulation of group I mGluRs was found to increase GluR1 phosphorylation of Ser831 and Ser845 in phospholipase C (PLC)-coupled Ca(2+) cascades. Interactions of protein kinases activated by intracellular Ca(2+) release downstream to PLC modulate the phosphorylation state of GluR1 on Ser831 and Ser845: phosphorylation of GluR1 on Ser831 is up-regulated by the protein kinase C and calcium-calmodulin-dependent protein kinase (CaMK)/c-Jun N-terminal kinase (JNK) pathways, whereas phosphorylation of GluR1 on Ser845 is up-regulated by the protein kinase A (PKA), PKA/ERK1/2, and PKA/JNK pathways. The phosphorylation state of GluR1 on Ser831 and Ser845 and the activity of protein kinases are further regulated by protein phosphatases. These data suggest that GluR1 phosphorylation of Ser831 and Ser845 via stimulation of group I mGluRs is regulated by the interactions of PLC-coupled protein kinases and protein phosphatases in the dorsal striatum.
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PMID:Activation of group I metabotropic glutamate receptors increases serine phosphorylation of GluR1 alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the rat dorsal striatum. 1925 22

Changes in synaptic strength mediated by ionotropic glutamate N-methyl-D-asparate (NMDA) receptors is generally considered to be the molecular mechanism underlying memory and learning. NMDA receptors themselves are subject to regulation through signaling pathways that are activated by G-protein-coupled receptors (GPCRs). In this study we investigate the ability of NMDA receptors to regulate the signaling of GPCRs by focusing on the G(q/11)-coupled M(3)-muscarinic receptor expressed endogenously in mouse cerebellar granule neurons. We show that NMDA receptor activation results in the phosphorylation and desensitization of M(3)-muscarinic receptors through a mechanism dependent on NMDA-mediated calcium influx and the activity of calcium-calmodulin-dependent protein kinase II. Our study reveals a complex pattern of regulation where GPCRs (M(3)-muscarinic) and NMDA receptors can feedback on each other in a process that is likely to influence the threshold value of signaling networks involved in synaptic plasticity.
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PMID:N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons. 1933 41

This review addresses the localized regulation of voltage-gated ion channels by phosphorylation. Comprehensive data on channel regulation by associated protein kinases, phosphatases, and related regulatory proteins are mainly available for voltage-gated Ca2+ channels, which form the main focus of this review. Other voltage-gated ion channels and especially Kv7.1-3 (KCNQ1-3), the large- and small-conductance Ca2+-activated K+ channels BK and SK2, and the inward-rectifying K+ channels Kir3 have also been studied to quite some extent and will be included. Regulation of the L-type Ca2+ channel Cav1.2 by PKA has been studied most thoroughly as it underlies the cardiac fight-or-flight response. A prototypical Cav1.2 signaling complex containing the beta2 adrenergic receptor, the heterotrimeric G protein Gs, adenylyl cyclase, and PKA has been identified that supports highly localized via cAMP. The type 2 ryanodine receptor as well as AMPA- and NMDA-type glutamate receptors are in close proximity to Cav1.2 in cardiomyocytes and neurons, respectively, yet independently anchor PKA, CaMKII, and the serine/threonine phosphatases PP1, PP2A, and PP2B, as is discussed in detail. Descriptions of the structural and functional aspects of the interactions of PKA, PKC, CaMKII, Src, and various phosphatases with Cav1.2 will include comparisons with analogous interactions with other channels such as the ryanodine receptor or ionotropic glutamate receptors. Regulation of Na+ and K+ channel phosphorylation complexes will be discussed in separate papers. This review is thus intended for readers interested in ion channel regulation or in localization of kinases, phosphatases, and their upstream regulators.
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PMID:Supramolecular assemblies and localized regulation of voltage-gated ion channels. 1934 11

Gonadotropin-releasing hormone (GnRH) neurons are critical to controlling fertility. In vivo, estradiol can inhibit or stimulate GnRH release depending on concentration and physiological state. We examined rapid, nongenomic effects of estradiol. Whole-cell recordings were made of GnRH neurons in brain slices from ovariectomized mice with ionotropic GABA and glutamate receptors blocked. Estradiol was bath applied and measurements completed within 15 min. Estradiol from high physiological (preovulatory) concentrations (100 pm) to 100 nm enhanced action potential firing, reduced afterhyperpolarizing potential (AHP) and increased slow afterdepolarization amplitudes (ADP), and reduced I(AHP) and enhanced I(ADP). The reduction of I(AHP) was occluded by previous blockade of calcium-activated potassium channels. These effects were mimicked by an estrogen receptor (ER) beta-specific agonist and were blocked by the classical receptor antagonist ICI182780. ERalpha or GPR30 agonists had no effect. The acute stimulatory effect of high physiological estradiol on firing rate was dependent on signaling via protein kinase A. In contrast, low physiological levels of estradiol (10 pm) did not affect intrinsic properties. Without blockade of ionotropic GABA and glutamate receptors, however, 10 pm estradiol reduced firing of GnRH neurons; this was mimicked by an ERalpha agonist. ERalpha agonists reduced the frequency of GABA transmission to GnRH neurons; GABA can excite to these cells. In contrast, ERbeta agonists increased GABA transmission and postsynaptic response. These data suggest rapid intrinsic and network modulation of GnRH neurons by estradiol is dependent on both dose and receptor subtype. In cooperation with genomic actions, nongenomic effects may play a role in feedback regulation of GnRH secretion.
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PMID:Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype. 1940 28

Ethanol (EtOH) modulates synaptic efficacy in various brain areas, including the cerebellum, which plays a role in motor coordination. Previous studies have shown that EtOH enhances tonic inhibition of cerebellar granule cells, which is one of the possible reasons for the alcohol-induced motor impairment. However, the effects of EtOH on molecular layer interneurons (MLIs) in the mouse cerebellum have remained unknown. Here we found that MLIs were depolarized by EtOH through enhancement of hyperpolarization-activated cationic currents (I(h)). Under physiological conditions, a low EtOH concentration (3-50 mM) caused a small increase in the firing rate of MLIs, whereas, in the presence of blockers for ionotropic glutamate and GABA receptors, EtOH (>or=10 mM) robustly enhanced MLI firing, suggesting that synaptic inputs, which seem to serve as the phasic inhibition, could suppress the EtOH-mediated excitation of MLIs and Purkinje cells (PCs). Even in the absence of synaptic blockers, a high EtOH concentration (100 mM) markedly increased the firing rate of MLIs to enhance GABAergic transmission. Furthermore, 100 mM EtOH-facilitated miniature IPSCs via a mechanism that depended on intracellular cyclic AMP, voltage-dependent Ca(2+) channels, and intracellular Ca(2+) stores, but was independent of I(h) or PKA. The two distinct effects of a high EtOH concentration (>or=100 mM), however, failed to attenuate the EtOH-induced strong depolarization of MLIs. These results suggest that acute exposure to a low EtOH concentration (<or=50 mM) enhanced GABAergic synaptic transmission, which suppressed the EtOH-evoked excitation of MLIs and PCs, thereby maintaining precise synaptic integration of PCs.
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PMID:Ethanol enhances both action potential-dependent and action potential-independent GABAergic transmission onto cerebellar Purkinje cells. 1942 45

Protein phosphorylation is an important mechanism for the posttranslational modulation of ionotropic glutamate receptors and is subject to regulation by changing synaptic inputs. In this study, we investigated the regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit phosphorylation by cocaine exposure in the rat dorsal striatum in vivo. We found that acute cocaine challenge followed by 6 days of repeated systemic injections of cocaine (20 mg/kg once daily) enhanced the sensitivity of the GluR1 subunit in its phosphorylation at serine 831 (Ser831) in the dorsal striatum. This enhancement of the sensitivity of Ser831 phosphorylation was reduced, at the receptor and ion channel level, by blocking (1) group I metabotropic glutamate receptors (mGluRs), (2) N-methyl-D-aspartate receptors, and (3) L-type voltage-operated Ca(2+) channels. Similar reduction of the enhancement was also induced, at the protein kinase level, by inhibiting (1) protein kinase C, (2) calcium/calmodulin-dependent protein kinases, and (3) c-Jun N-terminal kinases. In addition, inhibition of protein phosphatase 1/2A or calcineurin increased GluR1-Ser831 phosphorylation in the dorsal striatum of normal rats, whereas inhibition of these phosphatases did not further enhance the Ser831 phosphorylation in rats pretreated with 7 daily injections of cocaine. These data suggest that the phosphorylation of AMPA receptor GluR1 subunits at Ser831 is subject to upregulation by acute and repeated cocaine administration. Complex signaling integrations among glutamate receptors, Ca(2+) channels, protein kinases, and protein phosphatases participate in this upregulation.
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PMID:Alterations in AMPA receptor phosphorylation in the rat striatum following acute and repeated cocaine administration. 1955 63

Intracellular mechanisms underlying the functional suppression of ionotropic glutamate receptors by activation of metabotropic glutamate receptors were investigated in cultured chick Purkinje neurons. The intracellularly recorded depolarization induced by L-AMPA (an ionotropic glutamate receptor agonist, (S)-alpha-amino-4-hydroxy-5-methyl-4-isoxazolepropionic acid) and the L-AMPA-induced inward current recorded by whole-cell voltage clamping were used. L-AMPA responses were suppressed by trans-ACPD (a selective agonist of metabotropic glutamate receptor, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid) for various durations, with the longest duration about 60 min. This trans-ACPD effect was antagonized by l-(+)-2-amino-3-phosphonopropionic acid (a metabotropic glutamate receptor antagonist) and N(G) -monomethyl-L-arginine (a nitric oxide synthase inhibitor). Sodium nitroprusside, 3-morpholinosydnonimine (nitric oxide donors), and potassium ferricyanide mimicked trans-ACPD, and effects of trans -ACPD, sodium nitroprusside, and 3-morpholinosydnonimine were blocked by hemoglobin (a nitric oxide scavenger) but not by methemoglobin, while the effect of potassium ferricyanide was not affected by either hemoglobin or methemoglobin. 8-Bromo-cGMP also suppressed L-AMPA responses. KT5823 (a protein kinase G inhibitor) antagonized effects of trans-ACPD, 8-bromo-cGMP, and sodium nitroprusside. Phorbol 12,13-diacetate (a protein kinase C activator) also suppressed L-AMPA responses, and phorbol 12,13-diacetate plus trans-ACPD or phorhol 12,13-diacetate plus sodium nitroprusside showed an additive effect. Calphostin C and polymyxin B (protein kinase C inhibitors) antagonized the effect of trans-ACPD. These results suggest that activation of metabotropic glutamate receptors leads to the functional suppression of L-AMPA-sensitive ionotropic glutamate receptors in chick Purkinje neurons, and trans-ACPD-induced suppression of L-AMPA responses can be mimicked by activation of protein kinase G and/or protein kinase C. The involvement of nitric oxide in the trans-ACPD effect is discussed.
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PMID:Intracellular Mechanisms Underlying the Suppression of AMPA Responses by trans-ACPD in Cultured Chick Purkinje Neurons. 1991 44

Endogenous ghrelin and its synthetic counterpart hexarelin are peptide GH secretagogues (GHS) that exert a positive ionotropic effect in the cardiovascular system. The mechanism by which GHS modulate cardiac electrophysiology properties to alter myocyte contraction is poorly understood. In the present study, we examined whether GHS regulates the transient outward potassium current (I(to)) as well as the putative intracellular signaling cascade responsible for such regulation. GHS and experimental agents were applied locally onto freshly isolated adult Sprague-Dawley rat ventricular myocytes and action potential morphology and I(to) was recorded using nystatin-perforated whole-cell patch-clamp recording technique. Under current clamp, ghrelin and hexarelin (10 nm) significantly prolonged action potential duration. Under voltage clamp, hexarelin and ghrelin inhibited I(to) in a concentration-dependent manner. This inhibition was abolished in the presence of the GHS receptor (GHS-R) antagonist [D-Lys(3)]GH-releasing peptide-6 (10 microm) and GHS-R1a-specific antagonist BIM28163 (1 microm). GHS-induced I(to) inhibition was totally reversed by the phospholipase C inhibitor U73122 (5 microm) and protein kinase C inhibitors GO6983 (1 microm) and calphostin C (0.1 microm) but not by the cAMP antagonist Rp-cAMP (100 microm) or the PKA inhibitor H89 (1 microm). We conclude that hexarelin and ghrelin activate phospholipase C and protein kinase C signaling cascade through the stimulation of the GHS-R, resulting in a decrease in the I(to) current and subsequent prolongation of action potential duration.
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PMID:Growth hormone secretagogues reduce transient outward K+ current via phospholipase C/protein kinase C signaling pathway in rat ventricular myocytes. 2005 29


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