Molecular Biology of Voltage-Gated K+Channels

Abstract

Voltage-gated K+ (Kv) channels may be assembled from various subunits as homoor heteromultimers. The pore-forming α-subunits are integral membrane proteins, which express functional tetrameric Kv channels in heterologous expression systems. Three main families encoding Kv channel α-subunits have been detected related to the Drosophila genes Shaker and ether-a-go-go and the human KvLQT1 (KCNQ1) gene. Members of each family contribute to cardiac Kv channels and to cardiac action potential repolarization. Auxiliary subunits do not express functional Kv channels by themselves. They associate with α-subunits and may modulate Kv channel properties, including voltage dependence of activation and inactivation, deactivation, single-channel conductance, recovery from inactivation, and pharmacology. Auxiliary β-subunits have a structure which suggests that they may function as NADPH-dependent oxidoreductases. Whether this putative enzymatic activity is independent of the association of β-subunits with the pore-forming α-subunits is not known. Auxiliary γ-subunits are similar in sequence and topology to Shaker-related α-subunits but yield functional Kv channels only when coexpressed with certain α-subunits. In most cases, however, the exact subunit compositions of native Kv channels have not been elucidated. Therefore, it is still difficult to know which of the cloned Kv channels contribute to the different components of outward K+ current in cardiac myocytes. In only a few cases has the combination of human genetics, molecular biology, electrophysiology, and pharmacology provided a clear-cut identification of the a and auxiliary subunits that contribute to native K+ currents.