A New Family of Voltage-gated Potassium Channel Regulatory Subunits Accessory subunits and regulatory modifications are required to achieve normal function of voltage-gated potassium (Kv) channels in vivo. The reasons are clear. Accessory subunits and regulatory modifications (such as phosphorylation) alter pore-forming subunits to determine tissue specific protein expression, gating kinetics, unitary conductance, ion selectivity, regulation and pharmacology of mixed complexes. Thus, disease-associated mutations in accessory subunits and regulatory motifs have been seen to cause life- threatening cardiac arrhythmias, neuromuscular diseases like epilepsy and periodic paralysis. This application is based on our recent work demonstrating that the ubiquitous, small, ubiquitin-related modifier proteins (SUMOs, -100 amino acids) are an unrecognized class of accessory subunits that regulate potassium channels by reversible covalent modification in the plasma membrane. This application is based on preliminary data indicating that SUMOs directly influence excitation by modification and regulation of the Kv2.1, Kv4.3 and KChlP2. The proposed studies seek to describe regulation of these Kv channels by the SUMO pathway in mechanistic detail and to elucidate effects on physiology through experiments of cloned channels in experimental cells and native currents in primary cells from rat brain. We argue Kv channel regulation by sumoylation merits such scrutiny because (a) it appears to be important to normal physiology;(b) a new mechanism of ion channel regulation will be elucidated;and, (c) studies of accessory subunits/regulatory modifications have been the basis for diagnostic and therapeutic interventions to improve human health. This revised application seeks to address concerns raised in the first review cycle.