Mechanisms Controlling Kv channel Surface Density in Cardiac Myocytes.

Abstract

Conventional antiarrhythmic drugs target the ion permeability of channels. This therapeutic strategy, however, is limited by proarrhythmia in the ventricles due to a lack of ion channel selectivity and overlap in channel expression. Kv1.5 (KCNA5) mediates the ultrarapid potassium current (IKur) that controls atrial action potential duration. Given its atrial-specific expression and alterations in human AF, Kv1.5 has emerged as a promising pharmacological target for the treatment of AF. The research presented here revealed a novel effect of antiarrhythmic drugs in the acute modulation of surface channel density. This modulation was subunit-dependent and stereospecific and demonstrated partial, but incomplete overlap in the amino acid requirements for pore block and channel internalization, highlighting the potential for channel trafficking as a novel therapeutic approach. A necessary step in the development of novel agents that selectively modulate trafficking pathways is identification of the cellular machinery controlling surface density, of which little is yet known. Here, we show that the unconventional myosin motors Va and Vb controlled both the cell surface density of Kv1.5 and the Kv1.5-encoded IKur current in myocytes, demonstrating both functional distinction and subunit selectivity. Together, these data highlight the potential for new compounds that selectively alter the membrane stability of Kv1.5 as a means to gain atrial selectivity in the treatment of AF and as a novel approach for treating other cardiovascular arrhythmias.Ph.D.PharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89852/1/smschu_1.pd