MICHAEL C. SANGUINETTI
Michael C. Sanguinetti
email: sanguinetti@cvrti.utah.edu		 Professor of Physiology

The Sanguinetti Lab
Molecular Neuroscience
Neurobiology of Disease

B.S. 1976, Humboldt State University; M.S. 1978, San Jose State University; PhD. 1982, University of California, Davis; Postdoctoral Fellow, 1982-1984, University of Rochester.

RESEARCH:

Ionic basis of cardiac excitability; mechanisms of ion channel gating; mechanisms of channel block by drugs

Rhythmic contraction of the heart is caused by the opening and closing of a plethora of membrane-bound, ion-specific channels that conduct outward or inward currents. Dysfunction of any one of these channels can lead to fatal arrhythmias. The rapid (IKr) and slow (IKs) delayed rectifier K currents mediate repolarization during the plateau phase of the action potential and mutations in the genes encoding these channels (e.g., HERG, KCNQ1, KCNE1) cause inherited forms of cardiac arrhythmia. We use site-directed mutagenesis of cloned channels and voltage clamp techniques to study the molecular basis of potassium channel dysfunction caused by these mutations.

Voltage-gated channels such as the rapid delayed rectifier channel (hERG) open in response to membrane depolarization. In contrast, the pacemaker channel (e.g., HCN2) opens in response to membrane hyperpolarization. We are investigating the molecular mechanisms that determine the reversed polarity of the voltage sensor-activation coupling in these channels.

The availability of cloned channels and the ease of molecular biology has enabled the elucidation of the molecular determinants of ion channel block by drugs. We are investigating the physicochemical properties of the hERG, KCNQ1 and Kv1.5 channel binding site.

Selected Publications

Fernandez, D., Sargent, J., Sachse, F.B., and Sanguinetti, M.C. (2008) Structural basis for ether-a-go-go-related gene K+ channel subtype-dependent activation by niflumic acid. Molecular Pharmacology, 73:1159-1167.

Perry, M. and Sanguinetti, M.C. (2008) A single amino acid difference between ether-a-go-go-related gene channel subtypes determines differential sensitivity to a small molecule activator. Molecular Pharmacology, 73:1044-1051.

Perry, M., Sachse, F., and Sanguinetti, M.C. (2007) Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator. Proceedings of the National Academy of Sciences, USA, 104:13827-13832.

Cheng, L., Kinard, K., Rajamani, R., and Sanguinetti, M.C. (2007) Molecular mapping of the binding site for a blocker of HCN2 pacemaker channels. Journal of Pharmacology and Experimental Therapeutics, 322(3):931-939.

Decher, N., Renigunta, V., Zuzarte, M., Soo, M., Heinemann, S.H., Daut, J., Timothy, K.W., Keating, M.T., Sanguinetti, M.C., and Splawski, I. (2007) Impaired interaction between the slide helix and the C-terminus of Kir2.1: a novel mechanism of Andersen syndrome. Cardiovascular Research, 75:748-757.

Antzelevitch, C., Pollevick, G.D., Cordeiro, J.M., Casis, O., Sanguinetti, M.C., et al. (2007) Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation, 115(4):442-449.

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