title: Ca2+/calmodulin potentiates I Ks in sinoatrial node cells by activating Ca2+/calmodulin-dependent protein kinase II.
abstract: 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 Ca(2+)/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 Ca(2+) concentration (pCa 7, Ca (+)) compared to that with a low Ca(2+) 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 Ca(2+)-dependent manner. Intracellular application of a specific Ca(2+)/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 Ca(2+). Similarly, bath application of another inhibitor, KN-93 (1 μM) also significantly suppressed I Ks. Finally, the stimulatory action on I Ks of Ca(2+)/CaM was abolished by pretreatment with KN-93. Taken together, these observations suggest that Ca(2+)/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.
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xie
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
mesh_terms: D000200:Action Potentials; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002478:Cells, Cultured; D006168:Guinea Pigs; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012849:Sinoatrial Node / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002147:Calmodulin; D051657:KCNQ1 Potassium Channel; D010455:Peptides; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C503464:CaMKII inhibitor AIP; C072105:KN 93; D000096926:Benzenesulfonamides
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