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Associate Professor of Molecular Physiology and Biophysics
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BSEE, Electrical Engineering, University of Washington, SeattleMSE, Biomedical Engineering, University of Washington, SeattlePhD, Physiology and Biophysics, The University of Texas Medical Branch
Teaching Assistant, Physiology and Biophysics, The University of Texas Medical Branch, Galveston, TX
Biosciences Graduate ProgramDepartment of Molecular Physiology and Biophysics PhD
The primary focus in my laboratory is to understand the regulatory mechanism(s) of ion channels in excitable cells. Specifically, we are interested in the mechanism by which beta-adrenergic and muscarinic receptor agonists modulate ionic currents. Previous studies have suggested that in addition to the phosphorylation-dependent effects on ion channels, Gsalpha has an additional “direct” effect on the increase of cardiac sodium current that is independent but concurrent with phosphorylation effects. Our results strongly suggest that the number of functional Na+ channels increases in the membrane and that these channels are in caveolae (specifically those with the caveolin-3 isoform) (Yarbrough et al., 2002). Caveolae are dynamic omega-shaped invaginations whose membrane fusion and fission mechanisms are virtually unknown. These channel proteins do not migrate out of the caveolar membrane domain. Na+ channels within caveolae become functional when the caveolae “neck” opens to establish electrical continuity between the extracellular space and the intra-caveolae compartment. Our studies focus on determining the co-localization of Na+ (Nav1.5), Ca2+ (L-type or Cav1.2), and K+ (Kv1.5) channels in caveolae and the role of Gsalpha in the regulation of caveolae neck opening and closing. Our recent findings show that Gsalpha contains a critical histidine residue that plays an obligatory role in the caveolae neck opening.
Our animal models include enzymatically dissociated single myocytes from rabbit, rat and human hearts. We use several types of approaches to test our hypothesis. Some of these techniques include Western blot analysis, immunoprecipitation, confocal immunofluorescence, immuno-electron microscopy, and patch-clamping. The patch pipette voltage-clamp technique is used to determine changes in the biophysical properties of sodium, calcium and potassium currents as well as ultra high-resolution capacitance measurements.
These studies will provide new information into the mechanism of caveolae in heart and direct pathways for pharmacological interventions and therapeutic modalities of lethal arrhythmias.
Date Last Modified: 06/07/2014 -
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