Molecular Medicine Cardiac Small Conductance Ca -Activated K Channel Subunits Form Heteromultimers via the Coiled-Coil Domains in the C Termini of the Channels

Rationale: Ca 2؉-activated K ؉ channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca 2؉-activated K ؉ (SK or K Ca) channels in human and mouse cardiac myocytes that contribute functionally toward the shape and duration of cardiac action potentials. Three isoforms of SK channel subunits (SK1, SK2, and SK3) are found to be expressed. Moreover, there is differential expression with more abundant SK channels in the atria and pacemaking tissues compared with the ventricles. SK channels are proposed to be assembled as tetramers similar to other K ؉ channels, but the molecular determinants driving their subunit interaction and assembly are not defined in cardiac tissues. Objective: To investigate the heteromultimeric formation and the domain necessary for the assembly of 3 SK channel subunits (SK1, SK2, and SK3) into complexes in human and mouse hearts. ؉ current in atrial myocytes, which is important for cardiac repolarization. Conclusions: The data provide evidence for the formation of heteromultimeric complexes among different SK channel subunits in atrial myocytes. Because SK channels are predominantly expressed in atrial myocytes, specific ligands of the different isoforms of SK channel subunits may offer a unique therapeutic opportunity to directly modify atrial cells without interfering with ventricular myocytes. S mall conductance Ca 2ϩ-activated K ϩ (SK or K Ca 2) channels belong to a family of Ca 2ϩ-activated K ϩ channels (K Ca) that have been reported from a wide variety of cells. 1,2 K Ca channels represent a highly unique family of K ϩ channels in that they are directly gated by changes in intracellular Ca 2ϩ concentration and, hence, function to integrate changes in Ca 2ϩ concentration with changes in K ϩ conductance and membrane potentials. K Ca channels have been extensively studied in the central and peripheral nervous systems, where they mediate afterhyperpolarizations following action potentials 1,3 ; however, their functional importance in cardiac tissues is only beginning to be elucidated. 4 –11 Indeed, evidence for the existence of SK channels in the heart were first established by our laboratory 4,5 and has since been supported by work from others. 6,8 We have identified several isoforms of SK channel subunits in the heart including SK1, SK2, and SK3 (K Ca 2.1, 2.2, and 2.3) and have documented that SK channels are highly expressed and play important functional roles in atrial myocytes and pacemaking tissues compared …