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(Circulation Research. 2008;102:e1.)
© 2008 American Heart Association, Inc.

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AKAP150 Is Required for Stuttering Persistent Ca²⁺ Sparklets and Angiotensin II–Induced Hypertension

Manuel F. Navedo, Madeline Nieves-Cintrón, Gregory C. Amberg, Can Yuan, V. Scott Votaw, W. Jonathan Lederer, G. Stanley McKnight, Luis F. Santana

From the Departments of Physiology & Biophysics (M.F.N., M.N.-C., G.C.A., C.Y., V.S.V., L.F.S.) and Pharmacology (G.S.M.), University of Washington, Seattle; and Medical Biotechnology Center (W.J.L.), University of Maryland Biotechnology Institute, Baltimore. G.C. Amberg is currently with the Department of Biomedical Sciences, Colorado State University, Fort Collins.

Correspondence to Luis F. Santana, Department of Physiology & Biophysics, Box 357290, University of Washington, Seattle, WA 98195. E-mail santana{at}u.washington.edu

Hypertension is a perplexing multiorgan disease involving renal primary pathology and enhanced angiotensin II vascular reactivity. Here, we report that a novel form of a local Ca²⁺ signaling in arterial smooth muscle is linked to the development of angiotensin II–induced hypertension. Long openings and reopenings of L-type Ca²⁺ channels in arterial myocytes produce stuttering persistent Ca²⁺ sparklets that increase Ca²⁺ influx and vascular tone. These stuttering persistent Ca²⁺ sparklets arise from the molecular interactions between the L-type Ca²⁺ channel and protein kinase C at only a few subsarcolemmal regions in resistance arteries. We have identified AKAP150 as the key protein, which targets protein kinase C to the L-type Ca²⁺ channels and thereby enables its regulatory function. Accordingly, AKAP150 knockout mice (AKAP150^–/–) were found to lack persistent Ca²⁺ sparklets and have lower arterial wall intracellular calcium ([Ca²⁺]_i) and decreased myogenic tone. Furthermore, AKAP150^–/– mice were hypotensive and did not develop angiotensin II–induced hypertension. We conclude that local control of L-type Ca²⁺ channel function is regulated by AKAP150-targeted protein kinase C signaling, which controls stuttering persistent Ca²⁺ influx, vascular tone, and blood pressure under physiological conditions and underlies angiotensin II–dependent hypertension.

Key Words: L-type Ca²⁺ channels • protein kinase C • myogenic tone • total internal reflection fluorescence microscopy

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