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THOMAS W. COMOLLO
Biochemistry and Molecular Biology Program
M.S. 2008, UMDNJ – SHRP, Newark, NJ
B.A. 2004, Rutgers University, New Brunswick
Thesis Advisor: Roman Shirokov, Ph.D.
Department of Pharmacology & Physiology
Tuesday, May 5, 2015
11:00 A.M., MSB H-609b
CaV1.2 is an L-type, high voltage activated calcium channel expressed in neurons, endocrine, and cardiac cells. Its á1C subunit forms the pore. For channel membrane targeting, a â subunit must be included in the complex that also may contain an á2ä or a ã subunit. This study focuses on the role of ã subunits in CaV1.2 channels.
The ã1 is known to increase voltage dependent inactivation of CaV1.2. We have observed that a homologous ã6 ablates current with little effect on inactivation. Our theoretical modeling of the ã subunits suggests that this may be due to an increased flexibility in the ã1`s first extracellular loop. In addition, the ã6 contains a unique N-terminal region that may be responsible for the ablating effect on ionic current by restricting targeting to the plasma membrane. Unlike the wild type ã6, the ÄNã6 deletion affected neither ionic, nor gating currents, in our experiments. We also found that a construct coding for a peptide of the 30 most N-terminal residues causes a partial recovery of current when co-expressed with CaV1.2 that contains ã6.
Additionally, we provide evidence that the á1C N-terminus is involved in ablation of ionic current by the ã6. Possibly, the á1C N-terminus is a binding partner to the ã6 N-terminus. These two N-termini may also function by binding to an intermediary protein.
This research is fundamental for developing treatments of cardiovascular and psychiatric disorders because it offers clues to control of varying excitability and intracellular Ca2+ signaling in the heart and the brain.