Calcium influx via dihydropyridine-sensitive, voltage-gated L-type calcium channels plays a crucial role in the regulation of excitability, contraction, and gene expression in arterial smooth muscle. Our recent discovery that small clusters of L-type calcium channels can operate in a """"""""persistent"""""""" gating mode that create sites of nearly continual calcium influx (called """"""""persistent calcium sparklets"""""""") in smooth muscle has led to a paradigm shift, whereby calcium influx in these cells is predominantly controlled by this process in combination with rare voltage-dependent openings of individual L-type calcium channels. However, the role of persistent calcium sparklets on the regulation of local and global intracellular calcium as well as the molecular mechanisms underlying the activation and modulation of these calcium influx events in smooth muscle under physiological and pathophysiological conditions is virtually unknown. The proposed work will use new methods developed by our group to define the biophysical properties and functional roles of calcium sparklets in cerebral artery smooth muscle. Our preliminary results suggest that all proposed experiments are feasible and will provide important new information. The proposed work seeks to test three novel hypotheses.
In Specific Aim 1, we will test the hypothesis that calcium influx via calcium sparklets contributes to changes in local and global intracellular calcium concentration. The experiments in Specific Aim 2 will test the hypothesis that Cav1.2 channels underlie calcium sparklets in arterial smooth muscle. Finally, in Specific Aim 3, we build on the work in the previous two Specific Aims and test the hypothesis that persistent calcium sparklet activity is increased during hypertension. This work should provide the first integrated view of calcium sparklet-mediated signaling and their role in modulating cerebral arteries function and significantly enhance our understanding of arterial function in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085870-04
Application #
7798498
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$390,000
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Sato, Daisuke; Dixon, Rose E; Santana, Luis F et al. (2018) A model for cooperative gating of L-type Ca2+ channels and its effects on cardiac alternans dynamics. PLoS Comput Biol 14:e1005906
Gentil, Benoit J; O'Ferrall, Erin; Chalk, Colin et al. (2017) A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade. J Neuropathol Exp Neurol 76:789-799
Nieves-Cintrón, Madeline; Syed, Arsalan U; Buonarati, Olivia R et al. (2017) Impaired BKCa channel function in native vascular smooth muscle from humans with type 2 diabetes. Sci Rep 7:14058
Tajada, Sendoa; Moreno, Claudia M; O'Dwyer, Samantha et al. (2017) Distance constraints on activation of TRPV4 channels by AKAP150-bound PKC? in arterial myocytes. J Gen Physiol 149:639-659
Vivas, Oscar; Moreno, Claudia M; Santana, Luis F et al. (2017) Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage. Elife 6:
Ghosh, D; Syed, A U; Prada, M P et al. (2017) Calcium Channels in Vascular Smooth Muscle. Adv Pharmacol 78:49-87
Nieves-Cintrón, Madeline; Hirenallur-Shanthappa, Dinesh; Nygren, Patrick J et al. (2016) AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K(+) currents in ventricular myocytes following myocardial infarction. Cell Signal 28:733-40
Dickson, Eamonn J; Jensen, Jill B; Vivas, Oscar et al. (2016) Dynamic formation of ER-PM junctions presents a lipid phosphatase to regulate phosphoinositides. J Cell Biol 213:33-48
Moreno, Claudia M; Dixon, Rose E; Tajada, Sendoa et al. (2016) Ca(2+) entry into neurons is facilitated by cooperative gating of clustered CaV1.3 channels. Elife 5:
Dixon, Rose E; Moreno, Claudia M; Yuan, Can et al. (2015) Graded Ca²?/calmodulin-dependent coupling of voltage-gated CaV1.2 channels. Elife 4:

Showing the most recent 10 out of 32 publications