Persistent Calcium Sparklets in Vascular Smooth Muscle

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DESCRIPTION (provided by applicant): 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.