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"CONTROL OF L-TYPE CALCIUM CHANNELS BY 6 SUBUNIT"

by
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.
Associate Professor
Department of Pharmacology & Physiology

Tuesday, May 5, 2015
11:00 A.M., MSB H-609b


Abstract

CaV1.2 is an L-type, high voltage activated calcium channel expressed in neurons, endocrine, and cardiac cells. Its 1C subunit forms the pore. For channel membrane targeting, a subunit must be included in the complex that also may contain an 2 or a subunit. This study focuses on the role of subunits in CaV1.2 channels.
The 1 is known to increase voltage dependent inactivation of CaV1.2. We have observed that a homologous 6 ablates current with little effect on inactivation. Our theoretical modeling of the subunits suggests that this may be due to an increased flexibility in the 1`s first extracellular loop. In addition, the 6 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 6, the N6 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 6.
Additionally, we provide evidence that the 1C N-terminus is involved in ablation of ionic current by the 6. Possibly, the 1C N-terminus is a binding partner to the 6 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.


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