The channelopathies: novel insights into molecular and genetic mechanisms of human disease

Abstract

Ion channels are pore-forming proteins that provide pathways for the controlled movement of ions into or out of cells. Ionic movement across cell membranes is critical for essential and physiological processes ranging from control of the strength and duration of the heartbeat to the regulation of insulin secretion in pancreatic beta cells. Diseases caused by mutations in genes that encode ion channel subunits or regulatory proteins are referred to as channelopathies. As might be expected based on the diverse roles of ion channels, channelopathies range from inherited cardiac arrhythmias, to muscle disorders, to forms of diabetes. This series of reviews examines the roles of ion channels in health and disease.

Figure 1

Inherited mutations alter ion channel function and structure and cause human disease. Mutations may alter the permeation pathway (A) to inhibit the movement of ions through an open channel pore and may also alter ion channel gating by changing either the process by which channels open (activate) (B) or the process by which they inactivate (C). Transitions from the open to the inactivated state reduce the number of channels that are available to conduct ions. Mutations that destabilize the inactivated, nonconducting state of the channel are gain-of-function mutations and are common to diverse diseases, including LQTS, certain forms of epilepsy, and muscle disorders such as hyperkalemic paralysis.