Abstract
Voltage-gated K+ (Kv) channels are important in the physiology of both excitable and nonexcitable cells. The diversity in Kv currents is reflected in multiple Kv channel genes whose products may assemble as multisubunit heteromeric complexes. Given the fundamental importance and diversity of Kv channels, surprisingly little is known regarding the cellular mechanisms regulating their synthesis, assembly, and metabolism. To begin to dissect these processes, we have used the yeast two-hybrid system to identify cytoplasmic regulatory molecules that interact with Kv channel proteins. Here we report the cloning of a novel gene encoding a Kv channel binding protein (KChAP, for K+ channel-associated protein), which modulates the expression of Kv2 channels in heterologous expression system assays. KChAP interacts with the N termini of Kvalpha2 subunits, as well as the N termini of Kvalpha1 and the C termini of Kvbeta subunits. Kv2.1 and KChAP were coimmunoprecipitated from in vitro translation reactions supporting a direct interaction between the two proteins. The amplitudes of Kv2. 1 and Kv2.2 currents are enhanced dramatically in Xenopus oocytes coexpressing KChAP, but channel kinetics and gating are unaffected. Although KChAP binds to Kv1.5, it has no effect on Kv1.5 currents. We suggest that KChAP may act as a novel type of chaperone protein to facilitate the cell surface expression of Kv2 channels.
Highlights
The electrical properties of excitable cells are determined in large part by the voltage-gated Kϩ channels (Kv)1 they possess
Kv channels are important in many nonexcitable cells, where they may contribute to diverse processes such as volume regulation, hormone secretion, and activation by mitogens
With multiple Kv channel genes whose products may assemble as multisubunit heteromeric complexes (4 – 6), there may be hundreds of functionally distinct Kϩ channels
Summary
Voltage-gated Kϩ channel; kb, kilobase pair(s); GBP, Gu-binding protein; IP, immunoprecipitation. Kv subunit genes, cloned from heart [7,8,9,10] and brain [11,12,13], encode cytoplasmic proteins that form stable complexes with Kv␣1 subunits and exert multiple effects on Kv␣1 currents. A second effect of Kv subunits is to increase the surface expression of certain Kv␣1 channels This has been demonstrated both as an increase in the number of dendrotoxin-binding sites (for Kv1.2 transient expression) [15], as well as an increase in the number of functional channels [16]. Coexpression of KChAP with Kv␣2 subunits results in a dramatic enhancement of both total Kv2.1 protein and surface expression of functional Kv2 channels. The unique sequence and properties of KChAP suggest that it may belong to a novel class of proteins with “chaperone-like” properties
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