27 - Structure and Mechanism of Voltage-Gated Ion Channels

Abstract

This chapter explains the structure and mechanism of voltage-gated ion channels. The chapter discusses structure of ion channels and the current perspective about how these structures form transmembrane pores that gate to open and closed states in response to changes in membrane voltage. The chapter tries to address how macromolecular structures give rise to the important functional properties of ion channels—namely, the formation of transmembrane pores, the selective transport of specific ions, and the ability to open and close the pore; that is, functioning of ion channels as molecular mechanisms. The chapter also discusses purification and characterization of voltage-gated channels, channel structure investigation through manipulation of DNA sequences encoding channel polypeptides, investigation of molecular mechanisms of channel function, isoforms of voltage-gated channels as part of a large superfamily, and future directions and resolutions. The structure, mechanism, and expression of ion channels are currently intense areas of research interest. The first advances in these areas were made by the application of biochemical techniques to the problems of channel purification. The alpha (α) proteins apparently have all the molecular apparatus required for channel operation, while smaller associated subunits may play other roles in channel modulation, synthesis, or cellular localization. Purified material has also been considerable in the construction of probes to identify clones of channel-encoding DNA fragments. Other analyses of amino acid sequences have given clues regarding the mechanistically and structurally important domains of ion channels. One analysis was based on thermodynamic (hydropathy) considerations to identify possible membrane-spanning domains. These models have been tested using immunological and mutagenesis approaches, and candidate domains for ion selectivity, pore wall formation, gating, and modulation have been identified. It is mentioned that the detailed knowledge of the molecular mechanisms of channel function is still limited. The chapter concludes by stating that molecular studies have revealed an astonishing diversity of ion channels at all levels of organization. In particular, the genome of most organisms can express multiple channel isotypes, sometimes coexisting within the same living cell.