Harry A. Fozzard, MD

Otho S.A. Sprague Distinguished Service
Professor of Medical Sciences 
    & Emeritus: Medicine

Department of Neurobiology, Pharmacology  and Physiology
Committee on Cell Physiology

MD     Washington & Lee University
           Washington University Medical School 

Research Summary

Ion channels are intrinsic membrane proteins that mediate fast communication in muscle and heart. They are also important to a myriad of functions of non-excitable cells. This lab seeks to understand the structure-function of the voltage-gated ion channels as transducers of the membrane electric field into the opening and shutting of highly selective ion permeation paths through the membrane. The channels underlying excitability - the Na and Ca channels - are the products of a multigene family, composed of a large subunit of about 2000 amino acids, which contains the permeation properties, and several smaller subunits. They represent an ideal system for studying the molecular function of the channels because exquisitely detailed functional studies can be done on single native or cloned/expressed channels using patch clamp systems and the structure can be selectively altered by point mutation or chimera formation. We have combined this sort of study with molecular modeling, resulting in a detailed molecular model of drug and toxin binding sites. Because these ligands bind within the channel permeation path, the binding site itself a model of the pore of the channels and their selectivity filter, critical functions of permeation and ion selectivity. Our goal is to extend these studies to the molecular structures underlying the gating mechanisms of the channels and tothe binding sites for local anesthetic antiarrhythmic. This may allow rational drug design to modify the function of ion channels in patients with cardiac arrhythmias, ischemic injury to the heart or the brain, and other functions disordered by disease.

Some Selected Papers

Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms (1996). Physiological Reviews, 76, 887-926.

Modal behavior of the µ1 Na⁺ channel and effects of coexpression of the b1-subunit (1996). Biophysical Journal, 70, 2581-2592.

A structural motif for the voltage-gated potassium channel pore (1995). Proceedings of the National Academy of Science, 92, 9215-9219.

A µ-conotoxin-insensitive Na+ channel mutant:possible localization of a binding site at the outer vestibule (1995). Biophysical Journal, 69, 1657-1665.

The saxitoxin/tetrodotoxin binding site on the cloned rat brain IIa Na⁺ channels in the transmembrane electric field (1994). Biophysical Journal, 67, 1007-1014.

A structural model of the tetrodotoxin and saxitoxin binding site of the Na⁺ channel (1994). Biophysical Journal,66(1), 1-13.

Two phosphatase sites on the Ca²⁺ channel affecting different kinetic functions (1993). Journal of Physiology - London, 470, 73-84.

Divalent cation competition with [³H] saxitoxin binding to tetrodotoxin-resistant and -sensitive sodium channels. A two-site structural model of ion/toxin interaction (1993). Journal of General Physiology, 101(2), 153-82.

Mechanism of cAMP-dependent modulation of cardiac sodium channel current kinetics (1993). Circulation Research, 72(4), 807-815.

Phosphorylation restores activity of L-type calcium channels after rundown in inside-out patches from rabbit cardiac cells (1992). Journal of Physiology - London, 454, 673-688.

The cloned cardiac Na channel alpha-subunit expressed in Xenopus oocytes show gating and blocking properties of native channel (1992). Journal of Membrane biology, 130(1), 11-22.

A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties (1992). Science, 256(5060), 1202-1205.

Updated 10/18/02.