Stimulation of protein kinase C inhibits bursting in disease-linked mutant human cardiac sodium channels

Article

关键词: LONG-QT SYNDROME;    LIFE-THREATENING ARRHYTHMIAS;    NA+-CHANNEL;    INACTIVATION GATE;    SECONDARY STRUCTURE;    MODULATION;    PHOSPHORYLATION;    MECHANISM;    BRAIN;    SITE;   

DOI  :  10.1161/01.CIR.0000070936.65183.97

来源: SCIE

【 摘 要 】

Background-Mutations in SCN5A, the gene coding for the human cardiac Na+ channel alpha-subunit, are associated with variant 3 of the long-QT syndrome (LQT-3). Several LQT-3 mutations promote a mode of Na+ channel gating in which a fraction of channels fail to inactivate, contributing sustained Na+ channel current (I-sus), which can delay repolarization and prolong the QT interval. Here, we investigate the possibility that stimulation of protein kinase C (PKC) may modulate I-sus, which is prominent in disease-related Na+ channel mutations. Methods and Results-We measured the effects of PKC stimulation on Na+ currents in human embryonic kidney (HEK 293) cells expressing 3 previously reported disease-associated Na+ channel mutations (Y1795C, Y1795H, and DeltaKPQ). We find that the PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) significantly reduced I-sus in the mutant but not wild-type channels. The effect of OAG on Isus was reduced by the PKC inhibitor staurosporine (2.5 mumol/L), ablated by the mutation S1503A, and mimicked by the mutation S1503D. I-sus recorded in myocytes isolated from mice expressing DeltaKPQ channels was similarly inhibited by OAG exposure or stimulation of alpha(1)-adrenergic receptors by phenylephrine. The actions of phenylephrine on I-sus were blocked by the PKC inhibitor chelerythrine. Conclusions-We conclude that stimulation of PKC inhibits channel bursting in disease-linked mutations via phosphorylation-induced alteration of the charge at residue 1503 of the Na+ channel alpha-subunit. Sympathetic nerve activity may contribute directly to suppression of mutant channel bursting via alpha-adrenergic receptor-mediated stimulation of PKC.

【 授权许可】

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