Modulation of Kv7.1/KCNE1 Channel Activity by Navβ1

Abstract

KV7.1 is a voltage-gated potassium channel encoded by the gene KCNQ1. This channel is found in several organs, including the heart and the brain. In the mammalian heart, KV7.1 assembles with KCNE1 forming a channel complex that is critically important for ventricular repolarization. The activity of the KV7.1/KCNE1 complex results in the delayed rectifier current known as IKs. The voltage-gated sodium channel β type 1 subunit (NaVβ1) is also expressed in the mammalian heart. Mutations in this protein have been implicated in disorders such as epilepsy and cardiopathies, including Brugada syndrome and atrial fibrillation. The NaVβ1 subunit modulates the activity, trafficking, and expression of NaV channels. It has been shown that NaVβ1 also modulates channels from the KV1 and KV4 families, and KV7.2 channels. Preliminary data from our laboratory show that NaVβ1 modulates the activity of KV7.1. When expressed in Xenopus oocytes, KV7.1 channel-mediated K+-currents display a mild slow inactivation. These channels recover from inactivation during deactivation driven at negative voltage, displaying a “hook” like kinetics. In the presence of NaVβ1, the inactivation is remarkably enhanced, producing a strong resurgent conductance during deactivation at negative potentials. Furthermore, the deactivation rate is decreased, while activation remains seemingly unaltered. Since KV7.1, KCNE1 and NaVβ1 are expressed in the heart, we decided to investigate whether NaVβ1 could modulate KV7.1/KCNE1 activity. We found that expressing KCNE1 subunit seems to override the NaVβ1 subunit effect on KV7.1 channels. However, decreasing the relative expression of KCNE1 resulted in K+-currents that displayed features of the activity of both type of complexes. We therefore conclude that NaVβ1 can modulate the KV7.1/KCNE1 complex activity. Our work suggests that, in the heart, the interaction of KCNE1 with KV7.1 has evolved to avoid the effect of NaVβ1 on the channel, so preventing its inactivation.