The human ether-à-go-go related gene (hERG) encodes the pore-forming voltage-gated K+ channel that is essential for cardiac repolarization. Dr. Tsushima’s laboratory has previously characterized the endogenous expression of SNARE proteins in the mammalian heart, and the interaction of the SNARE protein syntaxin 1A (STX1A) with several cardiac ion channels. Here, we utilize a multi-disciplinary approach to describe the inhibitory effect of STX1A on hERG channel function. STX1A impairs hERG channel maturation and trafficking to the plasma membrane and induces a hyperpolarizing shift in the voltage-sensitivity of steady-state inactivation. We identify the residues involved in this protein-protein interaction through the use of hERG truncation mutations. We also describe the pharmacological and temperature-mediated rescue of hERG channel trafficking in the presence of STX1A. The regulation of cardiac ion channels by SNARE proteins represents a novel biological mechanism that may have universally intrinsic implications for normal and diseased heart function.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17438 |
| Date | 14 July 2009 |
| Creators | Mihic, Anton |
| Contributors | Tsushima, Robert G. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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