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"Regulation of L-type calcium channel CaV1.2 by 1 and 6 subunits"

by
Anna Angelova
Pharmacology and Physiology Program
M.S. 1992, Technical University of Varna (Varna, Bulgaria)



Thesis Advisor: Roman Shirokov, Ph.D.
Associate Professor
Department of Pharmacology and Physiology

Thursday, May 27, 2010
MSB H-609b, 10:00 A.M.


Abstract

Voltage-gated calcium channels (VGCC) are multimeric proteins composed of one pore-forming and voltage-sensing subunit (у) and 3 auxiliary subunits (, 2, and ). These channels are essential players in the generation of action potentials in excitable cells and in the voltage-dependent Ca2+ entry that is important for various physiological functions (e.g. muscle contraction and release of hormones and neurotransmitters).
The kinetic properties of the composite channel depend not only on the main у subunit, but are also modulated to different extents by the auxiliary subunits. In this work we investigated the effects of two subunits, ׃ and ׃, on L-type calcium channel CaV1.2 in a mammalian cell expression system.
The 1 subunit of the L-type VGCC serves as endogenous Ca2+ antagonist. It has a strong hyperpolarizing effect on the voltage-dependence of inactivation of CaV1.2 calcium channels. It has not been suspected that the functional effect of 1 is under cellular regulation. For the first time we established that this endogenous antagonist is regulated in a cell-cycle and cholesterol-dependent manner.
The ׃ subunit is very similar to ׃ in terms of sequence, but we established that its effects on CaV1.2 were not similar. We found that ׃ decreases the extent of CaV1.2 inactivation and leads to a depolarizing shift in the voltage-dependence of inactivation. We also show that 6 competes with 1 for interaction with the channel. We propose that in cells with both subunits, this competition leads to fine-tuning of the amount of Ca2+ entering the cell upon depolarization.


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