Erwin F. Shibata, Ph.D.

Associate Professor

University of Texas Medical Branch, 1984

Research Interests

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 b-adrenergic and muscarinic receptor agonists modulate ionic currents. Previous studies have suggested that in addition to the phosphorylation-dependent effects on ion channels, Ga_s 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⁺ (Na_v1.5), Ca²⁺ (L-type or Ca_v1.2), and K⁺ (K_v1.5) channels in caveolae and the role of Ga_s in the regulation of caveolae neck fusion and fission.

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 patchclamping. 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 fusion mechanism of caveolae in heart and direct pathways for pharmacological interventions and therapeutic modalities of lethal arrhythmias.

Representative References

1. Lu, T., Lee, H.-C., Kabat, J.A., and Shibata, E.F. Modulation of Rat Cardiac Sodium Channel by the Stimulatory G-Protein a-Subunit. J. Physiol. (Lond.) 518.2:371-384, 1999.

2. Yarbrough T., Lu, T., Lee, H.-C., and Shibata, E.F. Localization of Cardiac Sodium Channels in Caveolin-Rich Membrane Domains: Regulation of Sodium Current Amplitude. Circ. Res. 90:443-449, 2002.

3. Shibata, E.F., Brown, T.L.Y., Washburn, Z.W., Bai, J., Revak, T.J., Butters, C.A. Autonomic Regulation of Voltage-Gated Cardiac Ion Channels. Journal of Cardiovascular Electrophysiology, 17(5): S34-S42, 2006.