Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

Abstract

ABSTRACTMany voltage-dependent ion channels are regulated by accessory proteins, although the underlying mechanisms and consequences are often poorly understood. We recently reported a novel function of the amino acid transporter Slc7a5 as a powerful regulator of Kv1.2 voltage-dependent activation. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement (‘disinhibition’) with holding potentials more negative than −120 mV. Disinhibition of Kv1.1 is strongly attenuated by shRNA knockdown of endogenous Slc7a5. We investigated a variety of chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5. Overall, our study highlights additional Slc7a5-sensitive Kv1 subunits, and demonstrates that features of Slc7a5 sensitivity can be swapped by exchanging voltage-sensing domains.IMPACT STATEMENTThe voltage-sensing mechanism of a subfamily of potassium channels can be powerfully modulated in unconventional ways, by poorly understood regulatory partners.