ZHOU, MING, Ph.D. Assistant Professor of Physiology & Cellular Biophysics Molecular physiology and biophysics of potassium channel modulations. Office: Physicians & Surgeons | 12th floor | Room 401 Telephone: 212.342.3722 Fax: 212.305.5775 Email:mz2140@columbia.edu

Current Research

Voltage-dependent potassium channels (Kv) are integral membrane proteins that, in response to membrane voltage change, catalyze K+ to diffuse across the cell membrane. Kv channels are essential to many physiological processes such as the rhythmic beating of heart, the communication between neurons, and the secretion of hormones. One of most exciting and important topics in ion channel physiology is to understand the precisely controlled opening and closing, i.e., gating, of a channel. In a cell, Kv channels almost always assemble with other proteins and the gating is modulated by the association of these proteins. The focus and long-term goal of our research is to understand structural bases of gating modulation in Kv channels. Since many diseases such as certain forms of seizures, deafness, ataxia, and cardiac arrhythmias, for instance, are directly attributable to Kv channel dysfunction, results from our research will help develop new and safe therapeutic reagents targeting Kv channels.

Currently, we are working on modulation of Kv1 family channels by the associated beta subunit (Kvb). A composite model of the channel in complex with the beta subunit is shown in the figure. The amino acid sequence of Kvb is related to oxidoreductases, and the three-dimensional structure of Kvb shows the canonical structural fold of an oxidoreductase, a cofactor (NADPH) bound, and all the conserved catalytic residues in the right geometry for catalysis to happen. Deletion of Kvb gene in the fly and mouse causes phenotypes similar to channel deletions. In human, loss of Kvb gene has been linked to epilepsy and seizure. However, the physiological function of Kvb remains unresolved. Is Kvb really an enzyme? If it is, does the enzymatic reaction affect channel gating, or vice versa? To address these questions, we use a multidisciplinary approach, combining electrical recordings of channel function with protein biochemistry and X-ray crystallography.

A. Structure of Kv1.2 (blue) in complex with Kvβ2 (red) in ribbon representation (pdb code 2A79). Cell membrane is indicated by the straight lines.
B. Ribbon representation of Kvβ showing its structural fold (pdb code 1QRQ). The bound cofactor (cyan) and the conserved active site residues are shown in stick representation.

Selected Publications

Weng, J., Cao, Y., Moss, N., and Zhou, M. 2006. Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase. J. Biol. Chem., Vol 281(22), 15194-15200
Zhou, M., and MacKinnon, R. 2004. A mutant KcsA K+ channel with altered conduction properties and selectivity filter ion distribution. J. Mol. Biol., Vol 338(4), 839-46.

Zhou, M., Morais-Cabral, J., Mann, S., and MacKinnon, R. 2001. Potassium channel receptor site for the inactivation gate and quaternary amine blockers. Nature. Vol 411, 657-661.

Gulbis, J*, Zhou, M*, Mann, S, and MacKinnon, R. 2000. Structure of the cytoplasmic b subunit-T1 assembly of voltage-dependent K channels. Science. Vol 289, 123-127.

Grosman, C., Zhou, M., Auerbach, A. 2000. Mapping the conformational wave of acetylcholine receptor channel gating. Nature. Vol. 403, 773-776.

Zhou, M., Engel, A. G., and Auerbach A. 1999. Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndromes. Proc. Natl. Acad. Sci. U S A. 96(18):10466-71.

Salamone, F. N., Zhou, M., and Auerbach, A. 1999. A re-examination of adult mouse nicotinic acetylcholine receptor channel activation kinetics. J. Physiol. (Lond). Apr 15;516 (Pt 2):315-30.

Akk, G., Zhou, M., and Auerbach A. 1999. A mutational analysis of the acetylcholine receptor channel transmitter binding site. Biophys. J. Jan;76(1 Pt 1):207-18