A Role for DPPX Modulating External TEA Sensitivity of Kv4 Channels

Abstract

Shal-type (Kv4) channels are expressed in a large variety of tissues, where they contribute to transient voltage-dependent K ⁺ currents. Kv4 are the molecular correlate of the A-type current of neurons (I _SA), the fast component of I _TO current in the heart, and also of the oxygen-sensitive K ⁺ current (K _O2) in rabbit carotid body (CB) chemoreceptor cells. The enormous degree of variability in the physiological properties of Kv4-mediated currents can be attributable to the complexity of their regulation together with the large number of ancillary subunits and scaffolding proteins that associate with Kv4 proteins to modify their trafficking and their kinetic properties. Among those, KChIPs and DPPX proteins have been demonstrated to be integral components of I _SA and I _TO currents, as their coexpression with Kv4 subunits recapitulates the kinetics of native currents. Here, we explore the presence and functional contribution of DPPX to K _O2 currents in rabbit CB chemoreceptor cells by using DPPX functional knockdown with siRNA. Additionally, we investigate if the presence of DPPX endows Kv4 channels with new pharmacological properties, as we have observed anomalous tetraethylammonium (TEA) sensitivity in the native K _O2 currents. DPPX association with Kv4 channels induced an increased TEA sensitivity both in heterologous expression systems and in CB chemoreceptor cells. Moreover, TEA application to Kv4-DPPX heteromultimers leads to marked kinetic effects that could be explained by an augmented closed-state inactivation. Our data suggest that DPPX proteins are integral components of K _O2 currents, and that their association with Kv4 subunits modulate the pharmacological profile of the heteromultimers.