Harry A. Fozzard, M.D.

Primary:

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

Secondary:

Department of Medicine
Committee on Neurobiology
Committee on Cellular and Molecular Physiology

Education:

Degree	Year	Institution	Area
BS	1952	Washington and Lee University
MD	1956	Washington University
Residency	1961	Washington University	Medicine
Fellowship	1963	Washington University	Cardiology
Fellowship	1964	University of Bern	Physiology

Phone:	(773) 702-6789
E-Mail:	hafozzar@uchicago.edu
Address:	AMB M604 (MC 6094)
Web page:	http://med-www02.bsd.uchicago.edu/faculty_internet/faculty_profile.asp?empl_id=1017

Research Summary

Cellular and single-channel electrophysiology of cardiac muscle

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 to the binding sites for local anesthetic antiarrhythmics. 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.

Selected Publications

Hilbert, K., Sandtner, W., Kudlacek, O., Glaaser, I., Weiss, E., Kyle, J.W., French, R.J., Fozzard, H.A., Dudley, S.C. and Todt, H. The selectivity filter of the voltage-gated sodium channel is involved in channel activation. J. Biol. Chem., 276:27831-27839, 2001.

Hui, K., Lipkind, G., Fozzard, H.A. and French, R.J. Electrostatic and steric contributions to block of the skeletal muscle sodium channel by μ-conotoxin. J. Gen. Physiol., 119:45-54, 2002.

Khan, A., Romantseva, L., Lam, A., Lipkind, G. and Fozzard, H.A. Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block. J. Physiol., 543.1:71-84, 2002.

Hilbert, K., Sandtner, W., Kudlacek, O., Schreiner, B., Glaaser, I, Schutz, W., Fozzard, H.A., Dudley, S.C. and Todt, H. Interaction between fast and ultra-slow inactivation in the voltage-gated sodium channel. J. Biol. Chem., 277:37105-37115, 2002.

Lipkind, G.M. and Fozzard, H.A. Molecular modeling of interactions of dihydropyridines and phenylalkylamines with the inner pore of the L-type Ca channel. Molecular Pharm., 63: 499-511, 2003.

Sunami, A., Tracey, A., Glaaser, I.W., Lipkind, G.M., Hanck, D.A. and Fozzard, H.A. Accessibility of mid-segment domain IV S6 residues of the voltage-gated Na channel to methanethiosulfonate reagents. J. Physiol., 561:403-413, 2004.

Sandtner, W., Szendroedi, J., Zarrabi, T., Zebelin, E., Hilber, K., Glaaser, I., Fozzard, H.A., Dudley, S.C. and Todt, H. Lidocaine: A foot in the door of the inner vestibule prevents ultra-slow inactivation of a voltage-gated sodium channel. Molecular Pharmacol., 66:648-657, 2004.

Lipkind, G.M. and Fozzard, H.A. Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels. Molecular Pharmacol., 68:1611-1622, 2005.

Hilber, K., Sandtner, W., Zarrabi, T., Zebelin, E., Kudlacek, O., Fozzard, H.A., Todt, H. Selectivity filter residues contribute unequally to pore stabilization of voltage-gated sodium channels. Biochem., 44:13874-13882, 2005.

Khan, A., Kyle, J.W., Hanck, D.A., Lipkind, G.M. and Fozzard, H.A. Isoform-dependent interaction of voltage-gated sodium channels with protons. J. Physiol., 576:493-501, 2006.

Szendroedi, J., Sandtner, W., Zarrabi, T., Zebelin, E., Hilber, K., Dudley, S.C., Fozzard, H.A. and Todt, H. Speeding the recovery from ultra-slow inactivation of voltage-gated Na channels by metal ion binding to the selectivity filter: A foot-on-the-door? (in review), 2007.

McNulty, M., Edgerton, G., Shah, R.D., Hanck, D.A., Fozzard, H.A. and Lipkind, G.M. Charge at the Phe-1759 in the lidocaine binding site affects permeation in human cardiac voltage-gated sodium channels. J. Physiol., 581:741-755, 2007.

Updated 9/24/07.