Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
Nazlee Sharmin
School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, School of Dentistry, Edmonton Clinic Health Academy (ECHA), Edmonton, Canada
Grace Silver
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
Motoyasu Satou
Department of Biochemistry, Dokkyo Medical University School of Medicine, Tochigi, Japan; Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Yubin Hao
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
Toru Tateno
Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Victoria A Baronas
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Canada
Many voltage-dependent ion channels are regulated by accessory proteins. We recently reported powerful regulation of Kv1.2 potassium channels by the amino acid transporter Slc7a5. 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. Knockdown of endogenous Slc7a5 leads to larger Kv1.1 currents and strongly attenuates the disinhibition effect, suggesting that Slc7a5 regulation of Kv1.1 involves channel inhibition that can be reversed by supraphysiological hyperpolarizing voltages. We investigated chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5, and localize a specific position in S1 with prominent effects on Slc7a5 sensitivity. Overall, our study highlights multiple Slc7a5-sensitive Kv1 subunits, and identifies the voltage-sensing domain as a determinant of Slc7a5 modulation of Kv1 channels.
