Date of Award
L-type CaV1.3 calcium channels perform critical functions in auditory hair cells, cardiac pacemaker cells, and pancreatic β-cells, but little is currently known about how these channels are modulated by cell signaling mechanisms. To begin to address this issue, we have tested the ability of various G protein-coupled receptors (GPCRs) to modulate CaV1.3 expressed in a mammalian cell line. Expression plasmids encoding CaV1.3 and auxiliary calcium channel subunits α2-δb and β3 were transiently coexpressed in HEK293 cells along with plasmids encoding a single type of GPCR. As a control for functional expression of the GPCR, we performed parallel transfections of separate HEK293 cells with N-type calcium channels (CaV2.2), which display modulation by most GPCRs. Whole-cell patch-clamp recordings were used to monitor calcium channel activity under control conditions and during agonist-dependent receptor activation. Our results indicate that Gαq/11-coupled receptors (α1A-adrenergic, H1 histamine, M1 muscarinic acetylcholine, and neurokinin 1 (NK1) receptors) trigger profound inhibition of CaV1.3, whereas Gαi/o-coupled receptors (M2 muscarinic acetylcholine) and Gαs-coupled receptors (β2 adrenergic and D1 dopamine receptor) have no apparent effects on CaV1.3 activity. These results suggest that, in vivo, CaV1.3 may be modulated exclusively by Gαq/11-coupled GPCRs. This information may ultimately be useful in identifying pharmacological treatments for cardiac arrhythmias and disorders of hearing or insulin secretion.
Thomas, Brian, "Modulation of L-Type (CaV1.3) Calcium Channels" (2005). Undergraduate Honors Capstone Projects. 787.
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Departmental Honors Advisor
Capstone Committee Member