The long-term objective of this research proposal is to understand the molecular mechanisms involved in controlling hormone-induced Ca2+ influx. Receptor-operated and store-operated cation channels (ROC and SOC) represent vital Ca2+ influx pathways in almost all cellular systems. ROC and SOC play a crucial role in mediating numerous cellular functions including exocytosis and contraction. In adrenal chromaffin cells (ACC), circulating-hormone-activated ROC and SOC channels act in concert with voltage-gated Ca2+ channels to modulate exocytosis of catecholamines, essential regulators of vascular tone, cardiac output and heart rate. Little is known about the molecular nature of hormone-activated ROC and SOC in ACC. A growing body of evidence suggests that Canonical Transient Receptor Potential (TRPC) channels can form, or be a component of, ROC and SOC in various cell types. We have shown that TRPC channels are expressed in ACC and that over-expression of TRPCs increases sustained Ca influx and catecholamine secretion. A factor that determines Ca2+ influx through TRPCs is channel permeability. Regulation of TRPC channel permeability is not well understood, however, certain heteromers of TRPC channels exhibit reduced permeability. We hypothesize that TRPCs mediate hormone-evoked exocytosis in ACC and their heteromerization serves to regulate this ability. This project is aimed to identify the role and the regulation of endogenous TRPC channels in ACC. To do this we will use molecular biological, biochemical, patch-clamp and fluorescence imaging methods to address the following specific aims: (1) identify which TRPCs are endogenously expressed in ACC; (2) identify mechanisms regulating the expression of endogenous TRPCs in ACC; and (3) identify the molecular determinants governing heteromeric TRPC permeability. Together these studies will shed light on the mechanisms regulating circulating-hormone-activated catecholamine exocytosis in ACC. Catecholamines are crucial regulators of the cardiovascular function, therefore, understanding mechanisms involved in controlling secretion of catecholamines in ACC is an important health care issue. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083381-04
Application #
7455267
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Goldman, Stephen
Project Start
2006-12-04
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$367,766
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Chen, Xingjuan; Li, Wennan; Riley, Ashley M et al. (2017) Molecular Determinants of the Sensitivity to Gq/11-Phospholipase C-dependent Gating, Gd3+ Potentiation, and Ca2+ Permeability in the Transient Receptor Potential Canonical Type 5 (TRPC5) Channel. J Biol Chem 292:898-911
Chen, Xingjuan; Sun, Weiyang; Gianaris, Nicholas G et al. (2014) Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem 289:9600-10
Kumar, Sanjay; Chakraborty, Saikat; Barbosa, Cindy et al. (2012) Mechanisms controlling neurite outgrowth in a pheochromocytoma cell line: the role of TRPC channels. J Cell Physiol 227:1408-19
Touw, Ketrija; Chakraborty, Saikat; Zhang, Wenwu et al. (2012) Altered calcium signaling in colonic smooth muscle of type 1 diabetic mice. Am J Physiol Gastrointest Liver Physiol 302:G66-76
Chakraborty, Saikat; Berwick, Zachary C; Bartlett, Paula J et al. (2011) Bromoenol lactone inhibits voltage-gated Ca2+ and transient receptor potential canonical channels. J Pharmacol Exp Ther 339:329-40
Edwards, Jason M; Neeb, Zachary P; Alloosh, Mouhamad A et al. (2010) Exercise training decreases store-operated Ca2+entry associated with metabolic syndrome and coronary atherosclerosis. Cardiovasc Res 85:631-40
Hu, Guoqing; Oboukhova, Elena A; Kumar, Sanjay et al. (2009) Canonical transient receptor potential channels expression is elevated in a porcine model of metabolic syndrome. Mol Endocrinol 23:689-99
Obukhov, Alexander G; Nowycky, Martha C (2008) TRPC5 channels undergo changes in gating properties during the activation-deactivation cycle. J Cell Physiol 216:162-71
Liu, Che H; Wang, Tao; Postma, Marten et al. (2007) In vivo identification and manipulation of the Ca2+ selectivity filter in the Drosophila transient receptor potential channel. J Neurosci 27:604-15