|About GSBS | FAQ | Job Opportunities | Search UMDNJ|
Pharmacology and Physiology Program
M.S. 1992, Technical University of Varna (Varna, Bulgaria)
Thesis Advisor: Roman Shirokov, Ph.D.
Department of Pharmacology and Physiology
Thursday, May 27, 2010
MSB H-609b, 10:00 A.M.
Voltage-gated calcium channels (VGCC) are multimeric proteins composed of one pore-forming and voltage-sensing subunit (ƒÑƒ¡) and 3 auxiliary subunits (ƒÒ, ƒÑ2ƒÔ, and ƒ×). 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 ƒÑƒ¡ subunit, but are also modulated to different extents by the auxiliary subunits. In this work we investigated the effects of two ƒ× subunits, ƒ×ƒ¡ and ƒ×ƒ¦, on L-type calcium channel CaV1.2 in a mammalian cell expression system.
The ƒ×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 ƒ×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 ƒ×ƒ¦ subunit is very similar to ƒ×ƒ¡ in terms of sequence, but we established that its effects on CaV1.2 were not similar. We found that ƒ×ƒ¦ decreases the extent of CaV1.2 inactivation and leads to a depolarizing shift in the voltage-dependence of inactivation. We also show that ƒ×6 competes with ƒ×1 for interaction with the channel. We propose that in cells with both ƒ× subunits, this competition leads to fine-tuning of the amount of Ca2+ entering the cell upon depolarization.