Accessory Kvβ 1 Subunits Differentially Modulate the Functional Expression of Voltage-Gated K + Channels in Mouse Ventricular Myocytes

Abstract

Voltage-gated K + (Kv) channel accessory (β) subunits associate with pore-forming Kv α subunits and modify the properties and/or cell surface expression of Kv channels in heterologous expression systems. There is very little presently known, however, about the functional role(s) of Kv β subunits in the generation of native cardiac Kv channels. Exploiting mice with a targeted disruption of the Kvβ 1 gene (Kvβ 1 −/− ), the studies here were undertaken to explore directly the role of Kvβ 1 in the generation of ventricular Kv currents. Action potential waveforms and peak Kv current densities are indistinguishable in myocytes isolated from the left ventricular apex (LVA) of Kvβ 1 −/− and wild-type (WT) animals. Analysis of Kv current waveforms, however, revealed that mean±SEM I to,f density is significantly ( P ≤0.01) lower in Kvβ 1 −/− (21.0±0.9 pA/pF; n=68), than in WT (25.3±1.4 pA/pF; n=42), LVA myocytes, and that mean±SEM I K,slow density is significantly ( P ≤0.01) higher in Kvβ 1 −/− (19.1±0.9 pA/pF; n=68), compared with WT (15.9±0.7 pA/pF; n=42), LVA cells. Pharmacological studies demonstrated that the TEA-sensitive component of I K,slow , I K,slow2, is selectively increased in Kvβ 1 −/− LVA myocytes. In parallel with the alterations in I to,f and I K,slow2 densities, Kv4.3 expression is decreased and Kv2.1 expression is increased in Kvβ 1 −/− ventricles. Taken together, these results demonstrate that Kvβ 1 differentially regulates the functional cell surface expression of myocardial I to,f and I K,slow2 channels.