Modulation of heteromeric Kv1 channels by transmembrane lectins and redox.

Abstract

Voltage-gated potassium channels regulate cellular electrical activity and are influenced by a variety of stimuli including redox and accessory proteins. Kv1.2 channels are exquisitely sensitive to reducing agents, which promote an ‘inhibited’ gating mode characterized by a large depolarizing shift of voltage-dependence, decelerated activation kinetics, and use-dependent activation. Similarly, overexpression of Kv1.2 channels with transmembrane lectin LMAN2 recapitulates these functional outcomes. Kv1 family subunits assemble as heterotetramers with potential tremendous diversity of function and sensitivity. It is unclear whether or how redox or LMAN2 sensitivity of Kv1.2 influences other insensitive Kv1 subtypes when assembled in heteromeric channels. In this study, we tested the redox and LMAN2 sensitivity of a series of homomeric Kv1 and tandem-linked Kv1.2-1.X heteromeric channels. We report that among homomeric channels, redox and LMAN2 sensitivity is exclusive to Kv1.2, while in Kv1.2-containing heteromeric channels, this sensitivity persists. Redox and LMAN2 decelerated the activation kinetics of Kv1.2-containing channels but had no effect on the deactivation kinetics. Interestingly, some Kv1 subtypes (notably Kv1.1 and Kv1.4) appear to be more sensitive than others to Kv1.2-mediated modulation. In summary, these data indicate that Kv1.2 acts as an adaptor subunit capable of recruiting sensitivity to redox and certain accessory proteins. These findings broaden our understanding of the mechanism of modulation of heteromeric voltage-gated potassium channels.