Antiarrhythmic drug effects on sodium channel slow-type inactivation – investigation of interactions at the selectivity filter

The selective passage of ions through channels in cellular membranes provides the molecular basis for many cellular processes. This includes control of the initial phase of depolarizations that lead to contraction of the heart. Upon initiation of contraction, sodium ion channels open briefly, and then are inactivated by a portion of the protein that “”plugs”” the channel pore, preventing further ion passage. Recently, a much slower form of channel inactivation has been discovered, which researchers believe is controlled by a separate, co-existing mechanism. One theory suggests that slow inactivation occurs when the protein components responsible for the selective passage of sodium ions constrict, causing complete occlusion of the pore during periods of prolonged or rapid openings. Certain drug classes work by blocking sodium channels, such as local anesthetics and a sub-class of anti-arrhythmic drugs, both of which can be used to treat an irregular heartbeat. There is limited understanding of how these drugs affect, or are affected by, the slow inactivation process.