Voltage-gated ion channels control the electrical excitability of cells by allowing highly selective diffusion of charged ions across the plasma membrane in response to changes in membrane potential. In our lab we are particularly interested in voltage-gated potassium (Kv) channels - their molecular basis, physiological role, and association with inherited human disease. Kv channels consist of pore-forming alpha subunits and non-pore subunits such as the single transmembrane-domain KCNE peptides, which are the main focus of our research.

In human heart, the principal ventricular repolarization currents, IKr and IKs, both require KCNE peptides for normal function: KCNE2 associates with HERG alpha subunits to form IKr; KCNE1 with KCNQ1 to form IKs. Mutations in human KCNE1 and KCNE2 cause reduced K+ ion flux, compromised cardiac repolarization, and inherited and acquired long QT syndrome. These abnormalities predispose to ventricular fibrillation, torsades des pointes, and sudden death. A common polymorphism in KCNE2 increases the risk of acquired (Bactrim-induced) long QT syndrome. Mutation of KCNE3 is associated with familial periodic paralysis, a debilitating skeletal muscle disorder.

Our specific research activities include:
(1) Studying the structure/function of KCNE/alpha subunit complexes with a combination of site-directed mutagenesis, electrophysiological recording (patch clamp and two-electrode voltage clamp) and direct structure determination.
(2) Assessing the physiological role of promiscuity in KCNE/alpha subunit partnering by evaluating new partnerships using native current recording and subunit co-localization.
(3) Screening of cardiac arrhythmia patients for KCNE gene mutations to further understand the role of KCNE peptides in human cardiac pathophysiology.
(4) Development of novel small molecules that selectively block or open specific ion channels, with a view to developing therapeutic agents to combat electrical disorders such as cardiac arrhythmia and epilepsy.

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