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:2.7.11.17 (CaMKII)
4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional ionotropic nucleotidic receptors responding to diadenosine pentaphospate and nicotinic receptors responding to epibatidine coexpress in 19% of the total rat midbrain cholinergic terminals, as determined by the combination of immunological and microfluorimetric techniques. Activation of each independent receptor induces the intrasynaptosomal [Ca2+]i and acetylcholine (ACh) release in a dose-dependent way. The responses are inhibited by antagonists of the dinucleotide receptor and nicotinic receptors, thus confirming the involvement of specific receptors in both functions. Stimulation of single cholinergic terminal with both agonists altogether results in a significant decrease of the [Ca2+]i signaling compared with responses of each independent agonist. Inhibitory interaction between both receptors is reverted when one of them is blocked by specific antagonists, both in [Ca2+]i, and subsequent ACh release. The receptor's inhibitory cross talk confirm the involvement of calcium/calmodulin-dependent protein kinase II, CaMKII, as the inhibitory effects are reverted in the presence of the specific inhibitors KN-62 (2-[N-(4'-methoxybenzenesulfonyl)]-amino-N-(4'-chlorophenyl)-2-propenyl-N-methylbenzylamine phosphate) and KN-93 (N-(2-[N-[4-chlorocinnamyl]-N-methylaminomethyl]phenyl)-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide). These results demonstrate the existence of an efficient interaction between these two channel populations, opening a new understanding of the functioning of the cholinergic synaptic terminals or terminals containing other neurotransmitters but exhibiting these receptor types or ones that are similar.
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PMID:Interaction between dinucleotide and nicotinic receptors in individual cholinergic terminals. 1525 46

It is thought that activity-dependent changes in synaptic efficacy driven by biochemical pathways responsive to the action of the excitatory neurotransmitter glutamate are critical components of the mechanisms responsible for memory formation. In particular, the early activation of the NMDA (rNMDA) and AMPA (rAMPA) subtypes of ionotropic glutamate receptors has been demonstrated to be a necessary event for the acquisition of several types of memory. In the rat, consolidation of the long-term memory for a one-trial, step-down inhibitory avoidance task is blocked by antagonists of the rNMDA and rAMPA infused into the CA1 region of the dorsal hippocampus early after training and is associated with a rapid and reversible increase in the total number of [3H]AMPA binding sites. The learning-induced increase in [[3H]AMPA is accompanied by translocation of the GluR1 subunit of the rAMPA to the post-synaptic terminal together with its phosphorylation at Ser831. In addition, learning of the mentioned fear-motivated task induces the activation and rNMDA-dependent translocation of CaMKII to the post-synaptic density. Inhibition of this protein kinase as well as blockade of the rNMDA abolishes both the learning-induced translocation of GluR1 and its phosphorylation. Our data suggest that learning of an avoidance task enhances hippocampal rAMPA signaling through rNMDA and CaMKII-dependent mechanisms.
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PMID:Hippocampal glutamate receptors in fear memory consolidation. 1532 59

The ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor is densely distributed in the mammalian brain and is primarily involved in mediating fast excitatory synaptic transmission. Recent studies in both heterologous expression systems and cultured neurons have shown that the AMPA receptor can be phosphorylated on their subunits (GluR1, GluR2, and GluR4). All phosphorylation sites reside at serine, threonine, or tyrosine on the intracellular C-terminal domain. Several key protein kinases, such as protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and tyrosine kinases (Trks; receptor or nonreceptor family Trks) are involved in the site-specific regulation of the AMPA receptor phosphorylation. Other glutamate receptors (N-methyl-d-aspartate receptors and metabotropic glutamate receptors) also regulate AMPA receptors through a protein phosphorylation mechanism. Emerging evidence shows that as a rapid and short-term mechanism, the dynamic protein phosphorylation directly modulates the electrophysiological, morphological (externalization and internalization trafficking and clustering), and biochemical (synthesis and subunit composition) properties of the AMPA receptor, as well as protein-protein interactions between the AMPA receptor subunits and various intracellular interacting proteins. These modulations underlie the major molecular mechanisms that ultimately affect many forms of synaptic plasticity.
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PMID:Phosphorylation of AMPA receptors: mechanisms and synaptic plasticity. 1638 40

Dinucleoside polyphosphates or Ap(n)A are a family of dinucleotides formed by two adenosines joined by a variable number of phosphates. Ap(4)A, Ap(5)A, and Ap(6)A are stored together with other neurotransmitters into secretory vesicles and are co-released to the extracellular medium upon stimulation. These compounds can interact extracellularly with some ATP receptors, both metabotropic (P2Y) and ionotropic (P2X). However, specific receptors for these substances, other than ATP receptors, have been described in presynaptic terminals form rat midbrain. These specific dinucleotide receptors are of ionotropic nature and their activation induces calcium entry into the terminals and the subsequent neurotransmitter release. Calcium signals that cannot be attributable to the interaction of Ap(n)A with ATP receptors have also been described in cerebellar synaptosomes and granule cell neurons in culture, where Ap(5)A induces CaMKII activation. In addition, cerebellar astrocytes express a specific Ap(5)A receptor coupled to ERK activation. Ap(5)A engaged to MAPK cascade by a mechanism that was insensitive to pertussis toxin and required the involvement of src and ras proteins. Diadenosine polyphosphates, acting on their specific receptors and/or ATP receptors, can also interact with other neurotransmitter systems. This broad range of actions and interactions open a promising perspective for some relevant physiological roles for the dinucleotides. However, the physiological significance of these compounds in the CNS is still to be determined.
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PMID:Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways. 1668 66

The alpha-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) is an ionotropic glutamate receptor that governs most of excitatory synaptic transmission in neurons. In vitro biochemical assay has shown that calpain, a Ca2+-activated protease, can cleave AMPAR GluR1 subunits. Our physiological study found that calpain, which was activated by prolonged stimulation of the N-methyl-D-aspartate receptor (100 microM, 10 min), caused a substantial suppression of AMPAR currents in cortical neurons. Since the phosphorylation sites of GluR1 by several protein kinases are located in close proximity to the calpain cleavage sites, we investigated the effect of phosphorylation on the susceptibility of GluR1 to calpain cleavage. Interestingly, we found that the calpain regulation of AMPAR currents was diminished by inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) but was augmented by inhibition of protein phosphatase 1/2A (PP1/2A). In agreement with this, in vitro assay showed that the calpain-induced proteolytic cleavage of GluR1 C-terminal fusion protein was strongly potentiated by adding the purified active CaMKII, and GluR1 phosphorylated at Ser831 by CaMKII is much more sensitive to calpain cleavage. Taken together, our data suggest that calpain activation suppresses AMPA receptor currents via proteolytic cleavage of GluR1 subunits, and the susceptibility of AMPARs to calpain cleavage is determined by the phosphorylation state of GluR1 subunits, which is mediated by CaMKII-PP1/2A activity.
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PMID:The phosphorylation state of GluR1 subunits determines the susceptibility of AMPA receptors to calpain cleavage. 1742 97

The neurotransmitter gamma-aminobutyric acid (GABA) is an important modulator of gonadotropin-releasing hormone (GnRH), and consequently of reproduction. GABA, acting via ionotropic GABAA receptors, exerts a biphasic effect on GnRH secretion in immortalized GnRH cells. The initial increase in GnRH secretion is triggered by a sharp rise in [Ca2+]i, while the progressive decline of GnRH levels that follows is paralleled by reduced levels of intracellular cAMP. The experiments described here were designed to explore the potential signaling pathways involved in this novel GABAA ionotropic inhibition of cAMP synthesis in GT1-7 cells. Using RT-PCR and real-time PCR, we found that GT1-7 cells express 8 of 9 known membrane adenylyl cyclase (AC) isoforms, including a large proportion of AC3 and AC9, as well as AC5 and AC6, all of which are negatively regulated by increases in [Ca2+]i. In contrast, isoforms of AC that are positively regulated by [Ca2+]i were barely detectable (AC1) or undetectable (AC8). Pharmacological activation of L-type voltage-operated calcium channels with BayK 8644 produced a decrease in [cAMP]i similar to that induced by GABA, while blocking these calcium channels with verapamil reversed the effect of GABA on cAMP synthesis. Furthermore, blocking calcineurin with deltamethrin, FK-506 or cyclosporin A blocked the inhibitory effect of GABA on [cAMP]i, supporting the involvement of AC9 in this effect. In addition, blocking Ca2+/calmodulin-dependent protein kinase II (CamKII) with KN-62 partially reversed the action of GABA, suggesting that AC3 may also be involved in this effect. Finally, GABA increased phosphatase activity in a calcium-dependent manner, an effect blocked by calcineurin inhibitors. Collectively, our results show that the ionotropic action of GABA via the activation of GABAA receptors can decrease AC activity in immortalized GnRH neurons, and that the effect of GABA appears to be mediated by a transient increase in [Ca2+]i followed by activation of calcineurin and CamKII, leading to dephosphorylation of AC9 and phosphorylation of AC3, respectively, and subsequently reducing the synthesis of cAMP.
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PMID:GABA inhibition of cyclic AMP production in immortalized GnRH neurons is mediated by calcineurin-dependent dephosphorylation of adenylyl cyclase 9. 1755 Dec 63

Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are densely expressed in mammalian brain. They are actively involved in the regulation of normal cellular activity and synaptic plasticity, and are frequently linked to the pathogenesis of various mental illnesses. Like ionotropic glutamate receptors, group I mGluRs are subject to the regulation by protein phosphorylation. Accumulative data demonstrate sufficient phosphorylation of the intracellular mGluR1/5 domains at specific serine/threonine sites by protein kinase C in heterologous cells or neurons, which serves as an important mechanism for regulating the receptor signaling and desensitization. Emerging evidence also shows the significant involvements of G protein-coupled receptor kinases, Ca2+/calmodulin-dependent protein kinase II, tyrosine kinases, and protein phosphatases in controlling the phosphorylation status of group I mGluRs. This review analyzes the recent data concerning group I mGluR phosphorylation and the phosphorylation-dependent regulation of group I mGluR function. Future research directions in this area with newly available high throughput and proteomic approaches are also discussed in the end.
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PMID:Phosphorylation of group I metabotropic glutamate receptors (mGluR1/5) in vitro and in vivo. 1858 98

During the establishment of neural circuits, the axons of neurons grow towards their target regions in response to both positive and negative stimuli. Because recent reports show that Ca2+ transients in growth cones negatively regulate axonal growth, we studied how ionotropic ATP receptors (P2X) might participate in this process. Our results show that exposing cultured hippocampal neurons to ATP induces Ca2+ transients in the distal domain of the axon and the concomitant inhibition of axonal growth. This effect is mediated by the P2X7 receptor, which is present in the growth cone of the axon. Pharmacological inhibition of P2X7 or its silencing by shRNA interference induces longer and more-branched axons, coupled with morphological changes to the growth cone. Our data suggest that these morphological changes are induced by a signalling cascade in which CaMKII and FAK activity activates PI3-kinase and modifies the activity of its downstream targets. Thus, in the absence or inactivation of P2X7 receptor, axons grow more rapidly and form more branches in cultured hippocampal neurons, indicative that ATP exerts a negative influence on axonal growth. These data suggest that P2X7 antagonists have therapeutic potential to promote axonal regeneration.
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PMID:Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons. 1898 56

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

ATP, via purinergic P2X receptors, acts as a neurotransmitter and modulator in both the central and peripheral nervous systems, and is also involved in many biological processes, including cell proliferation, differentiation and apoptosis. Previously, we have reported that P2X7 receptor inhibition promotes axonal growth and branching in cultured hippocampal neurons. In this article, we demonstrate that the P2X7 receptor negatively regulates neurite formation in mouse Neuro-2a neuroblastoma cells through a Ca2+/calmodulin-dependent kinase II-related mechanism. Using both molecular and immunocytochemical techniques, we characterized the presence of endogenous P2X1, P2X3, P2X4 and P2X7 subunits in these cells. Of these, the P2X7 receptor was the only functional receptor, as its activation induced intracellular calcium increments similar to those observed in primary neuronal cultures, exhibiting pharmacological properties characteristic of homomeric P2X7 receptors. Patch-clamp experiments were also conducted to fully demonstrate that ionotropic P2X7 receptors mediate nonselective cation currents in this cell line. Pharmacological inhibition of the P2X7 receptor and its knockdown by small hairpin RNA interference resulted in increased neuritogenesis in cells cultured in low serum-containing medium, whereas P2X7 overexpression significantly reduced the formation of neurites. Interestingly, P2X7 receptor inhibition also modified the phosphorylation state of focal adhesion kinase, Akt and glycogen synthase kinase 3, protein kinases that participate in the Ca2+/calmodulin-dependent kinase II signalling cascade and that have been related to neuronal differentiation and axonal growth. Taken together, our results provide the first mechanistic insight into P2X7 receptor-triggered signalling pathways that regulate neurite formation in neuroblastoma cells.
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PMID:Ca2+/calmodulin-dependent kinase II signalling cascade mediates P2X7 receptor-dependent inhibition of neuritogenesis in neuroblastoma cells. 1968 70


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