Heteromultimer Formation in Native K+Channels

Abstract

Potassium channels in the cardiovascular system are, in all known cases, multisubunit membrane protein complexes. Typically, multiple pore-forming and voltage-and/or ligand-sensing polytopic transmembrane α-subunits are associated with nonconducting transmembrane or cytoplasmic auxiliary subunits. Cardiac K+ channel complexes can consist of up to 8–10 such polypeptide components whose presence and position within the channel complex determine the precise functional properties of the resultant channel. Unlike many well-characterized multisubunit membrane protein complexes (e.g., the muscle nicotinic acetylcholine receptor, the T-cell antigen receptor), native K+ channel complexes have variable quaternary structures, such that the differential assembly of component subunits can yield channels of distinct subunit composition and function. This complexity presents an especially interesting yet challenging task to biochemists and cell biologists interested in the quaternary structure of these proteins, and in more general aspects of membrane protein biosynthesis and structure. However, K+ channels offer an attractive experimental system for identifying potential novel mechanisms involved in the biosynthetic assembly and maturation of this family of proteins, which are clearly distinct from those multisubunit membrane proteins of invariant subunit composition previously studied. The analysis of the quaternary structure of native K+ channels is also of obvious importance to our understanding of K+ channel function, and therefore the molecular basis of electrical excitability, and for any drug discovery strategies that plan to utilize expression of cloned K+ channels to reconstitute relevant K+ channel protein complexes in cell lines for high-throughput screening.