|Rank||Professor, Chief, Division of Cardiology|
|SOM Address||Room 844
There are two main areas of focus in our laboratory: structure function studies of ion channels and the regulation of expression of ion channel proteins in heart disease and the electrophysiological consequences of this remodeling. We have studied the fundamental basis of permeation and regulation of gating in the voltage dependent Na channel for the past decade. We have discovered the critical role of cysteines in the pore as molecular determinants of ion selectivity and sensitivity to block by divalent cations and isoform-specific toxin blockers. We have more recently focused our attention on the role of the major molecular determinant of selectivity, the outer pore, on slow inactivation gating. Using site-directed mutagenesis, patch clamp recording and fluorescence measurements we have determined that molecular rearrangement of the outer pore is essential to the development of slow inactivation of the Na channel.
The second major area of interest is electrical remodeling that occurs in the context of structural heart disease. We have used several models of heart failure to study regional changes in cell surface electrical signaling and calcium handling using optical mapping techniques and cellular electrophysiological recording. We seek to understand the protein chemical and molecular basis of the alterations in electrophysiological properties by studying changes in the mRNA and protein expression of ion channels and transporters. We have developed a canine microarray for the broad-based study of gene expression in the structurally diseased heart.
- Yamagishi T, Chiamvimonvat N, Velez P, Li R, Hsu K, MarbἯspan>n E, Tomaselli GF. Molecular Architecture of the voltage-dependent Na channel-Functional evidence for alpha helices in the pores. J Gen Physiol 118:171-82, 2001.
- Deschenes I, Neyroud N, DiSilvestre D, Marban E, Yue DT, Tomaselli GF. Isoform-specific modulation of voltage-gated Na channels by calmodulin. Circ Research, 90-349-e57, 2002.
- Deschenes I, DiSilvestre D, Juang GJ, Wu R, An WF, Tomaselli GF. Regulation of Kv4.3 current by KChIP2 Splice Variants: A component to native Ito. Circulation 106:423-9, 2002.
- Deschenes I, Tomaselli GF. Modulation of Kv4.3 current by accessory subunits. FEBS Lett 528:183-8, 2002.
- Kondratiev A and Tomaselli GF. Altered gating and local anesthetic block mediated by residues in the I-S6 and II-S6 transmembrane segments of voltage-dependent Na channels. Mol Pharmacol, 64:741-52, 2003.
- Yung CK, Halperin V, Tomaselli GF, Winslow RL. Gene Expression Profiles in End-Stage Human Idiopathic Dilated Cardiomyopathy: Altered Expression of Apoptotic and Cytoskeletal Genes. Genomics 83:281-97, 2003.
- Akar FG, Wu RC, Deschenes I, Armoundas AA, Piacentino V, Houser SR, Tomaselli GF. Phenotypic Differences in the Transient Outward K+ Current in Human and Canine Ventricular Myocytes: Insights into the Molecular Composition of Ventricular Ito. Am J Physiol 286:H602-9, 2004.
- Akar FG, Spragg DD, Tunin RS, Kass DA, Tomaselli, GF. Cellular and Molecular Mechanisms Underlying Conduction Slowing in Non-ischemic Cardiomyopathy. Circ Res 95:717-25, 2004.