Published online before print January 3, 2008, doi: 10.1161/CIRCRESAHA.107.167809
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Submitted on September 7, 2007
Revised on December 13, 2007
Accepted on December 17, 2007
AKAP150 Is Required for Stuttering Persistent Ca2+ Sparklets and Angiotensin II–Induced Hypertension
Manuel F. Navedo ;
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.
* To whom correspondence should be addressed. 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 • and total internal reflection fluorescence microscopy
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