Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although it is widely accepted that afterdepolarizations initiate arrhythmias when action potentials are prolonged, the underlying mechanisms are unclear. In this study, we tested the hypothesis that action potential prolongation would raise intracellular calcium and thereby activate the arrhythmogenic transient inward current (Iti). Furthermore, given that Iti can be activated by sarcoplasmic reticulum Ca2+ release, we tested the hypothesis that inhibition of calmodulin (CaM) kinase would prevent Iti. Isolated rabbit ventricular myocytes were studied with whole-cell-mode voltage clamp. Stimulation with a prolonged action potential clamp, under near-physiological conditions, increased [Ca2+]i. Iti was reproducibly induced in 60 of 60 cells, but Iti was not seen with the use of a shorter action potential waveform (n=12). Iti was associated with a secondary elevation in [Ca2+]i. When [Ca2+]i buffering was enhanced by dialysis with BAPTA (20 mmol/L, n=9), no Iti was present. The Na+/Ca2+ exchanger was likely responsible for Iti, because Iti was inhibited by the Na+/Ca2+ exchanger inhibitory peptide XIP (10 micromol/L, n=6), but not by an inactive scrambled peptide (10 micromol/L, n=5) or by the Cl- current antagonist niflumic acid (10 to 40 micromol/L, n=9). Activator Ca2+ from the sarcoplasmic reticulum was essential for development of Iti, because it was prevented by pretreatment with ryanodine (10 micromol/L, n=6) or thapsigargin (1 micromol/L, n=6). Two different CaM kinase inhibitory peptides (n=16) and a CaM inhibitory peptide (n=4) completely suppressed Iti. These results are consistent with the hypothesis that CaM kinase plays a role in arrhythmias related to increased [Ca2+]i.
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PMID:Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. 1022 37

Nerve growth factor (NGF) was found to increase glutamate release in the developing visual cortex. We investigated the cellular mechanisms of this effect and its dependence on extracellular and intracellular Ca2+. The NGF-induced enhancement of glutamate release from superfused rat visual cortex synaptosomes required mild depolarization. Removal of external Ca2+ during depolarization with 15 mM K+ only halved the effect of NGF on glutamate release. NGF increased [Ca2+]i in K+-depolarized synaptosomes preloaded with fura-2AM both in the presence and in the absence of external Ca2+. The effects of NGF on glutamate release and [Ca2+]i elevation were prevented by an anti-TrkA receptor monoclonal antibody. NGF increased synaptosomal inositol (1,4,5)-triphosphate (InsP3) during depolarization and the InsP3 receptor antagonist heparin abolished the effect of NGF on evoked glutamate release both in the presence and in the absence of external Ca2+. The effect of NGF on the evoked glutamate release in Ca2+-free medium was abolished by dantrolene, a ryanodine receptor blocker, by CGP 37157, a blocker of the mitochondrial Na+/Ca2+ exchanger and by pretreatment of synaptosomes with caffeine. NGF significantly increased the depolarization-induced activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the subsequent phosphorylation of synapsin I in the absence of external Ca2+ and the NGF effect on evoked glutamate release was inhibited by the CaMKII inhibitors KN-93 and CaMKII 281-309 peptide but not by the MAP kinase inhibitor PD 98059. Thus, the effect of NGF on evoked glutamate release is linked to an increase in [Ca2+]i contributed by both Ca2+ entry and mobilization from InsP3-sensitive, ryanodine-sensitive and mitochondrial stores and to the subsequent activation of CaMKII.
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PMID:Cellular mechanisms of the acute increase of glutamate release induced by nerve growth factor in rat cerebral cortex. 1269 58

The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused hearts remains controversial. Although a decrease in the phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) was previously reported, experiments from our laboratory failed to detect this decrease. In an attempt to elucidate the cause for this discrepancy, experiments were performed in Langendorff-perfused rat hearts with two main goals: (1) To determine whether keeping pacing during ischemia, a protocol followed in other ischemia-reperfusion models, decreases the phosphorylation of PLB residues, below pre-ischemic values; (2) To investigate whether a maximal beta-adrenergic challenge allows to detect a decrease in the ability of PLB to be phosphorylated in ischemia-reperfused hearts. Hearts were submitted to a global ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during ischemia, and phosphorylation of PLB residues was assessed by immunodetection. The recovery of contractility upon reperfusion was lower in P vs. NP hearts. Ser16 of PLB, was phosphorylated at the end of ischemia in NP hearts. This increase appeared earlier in P hearts and was significantly diminished by catecholamine depletion and beta-blockade. Thr17 site was phosphorylated at the beginning of ischemia and the onset of reperfusion. The ischemia-induced phosphorylation of Thr17 was higher and more sustained in P vs. NP hearts, and inhibited by the calcium channel blocker, nifedipine, whereas the reperfusion-induced increase in Thr17 phosphorylation was similar in P and NP hearts and was significantly diminished by the Na+/Ca2+ exchanger inhibitor KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at any time during ischemia and reperfusion. However, the phosphorylation, inotropic and lusitropic response to beta-adrenergic stimulation was significantly decreased both in P and NP hearts.
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PMID:Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing during ischemia and response to a beta-adrenergic challenge. 1457 98