4.4 Article

Ca2+/calmodulin potentiates I Ks in sinoatrial node cells by activating Ca2+/calmodulin-dependent protein kinase II

Journal

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Volume 467, Issue 2, Pages 241-251

Publisher

SPRINGER
DOI: 10.1007/s00424-014-1507-1

Keywords

Calmodulin; CaMKII; Sinoatrial node cells; Delayed rectifier K+ current; KCNQ1

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Funding

  1. Grants-in-Aid for Scientific Research [25460287] Funding Source: KAKEN

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The slow component of the delayed rectifier K+ current (I (Ks)) plays an important role in the repolarization of action potentials in cardiac pacemaker cells and ventricular myocytes, and is regulated by various signaling pathways. Recent evidence has shown that calmodulin (CaM) is involved in modulation of diverse ion channels in cardiac myocytes under physiological and pathophysiological conditions. In the present study, we examined regulation of I (Ks) by Ca2+/CaM in guinea pig sinoatrial (SA) node cells using the whole-cell patch-clamp method. The density of I (Ks) was larger during intracellular dialysis with a higher Ca2+ concentration (pCa 7, Ca (+)) compared to that with a low Ca2+ concentration (pCa 10, Ca (-)). Intracellular application of CaM (400 nM) markedly potentiated I (Ks) with a Ca (+) pipette solution but not with a Ca (-) solution, thus showing that CaM potentiates I (Ks) in an intracellular Ca2+-dependent manner. Intracellular application of a specific Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, autocamtide-2 inhibitory peptide (AIP, 500 nM), markedly reduced I (Ks) activity in the presence of higher intracellular Ca2+. Similarly, bath application of another inhibitor, KN-93 (1 mu M) also significantly suppressed I (Ks). Finally, the stimulatory action on I (Ks) of Ca2+/CaM was abolished by pretreatment with KN-93. Taken together, these observations suggest that Ca2+/CaM stimulates I (Ks) in guinea pig SA node cells through activation of CaMKII. This enhancement of I (Ks) by CaMKII may be involved in modulation of SA node automaticity under physiological or pathophysiological condition.

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