Mutations affecting electro-mechanical coupling in KCNQ channels alter kinetics and voltage dependence of activation.

Abstract

The KCNQ voltage-gated potassium channel family serves multiple physiological functions, from regulating heartbeat (by KCNQ1) to controlling neuronal excitability (by KCNQ2-5). In KCNQ1 channels, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, pharmacology, and physiology of KCNQ1. However, whether all KCNQ channels share the same mechanism is unclear. Here, we provide functional evidence that KCNQ2/3 only conducts at the AO state, but the electro-mechanical (E-M) coupling mechanism is conserved between KCNQ1 and KCNQ2/3. We demonstrate that this conserved E-M coupling can be compromised by select epilepsy-linked mutations in KCNQ2/3 and also can be effectively targeted by the antiepileptic prototype drug retigabine, suggesting E-M coupling as a therapeutic target for epilepsy treatment. Interestingly, KCNQ1 and KCNQ2/3 exhibit distinct kinetics and voltage dependence of activation for the AO state. While these differences may have important implications for the primary physiological roles of KCNQ2/3 (modulation of neuronal excitability) versus KCNQ1 (repolarization of cardiac action potential), it remains unclear where they originate from. Here, we find that analogous mutations in the distal S6 of KCNQ1 and KCNQ2 both affect the AO state E-M coupling and lead to delays in current activation kinetics and right shifts in voltage dependence of activation. KCNQ2 mutations near this location are also found to be associated with epileptic encephalopathy. These results further support a common regulatory mechanism for KCNQ currents via E-M coupling and indicate the physiological relevance of altering AO state activation properties in KCNQ channels.