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

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 Ca signaling in arterial smooth muscle is linked to the development of angiotensin II–induced hypertension. Long openings and reopenings of L-type Ca channels in arterial myocytes produce stuttering persistent Ca sparklets that increase Ca influx and vascular tone. These stuttering persistent Ca sparklets arise from the molecular interactions between the L-type Ca channel and protein kinase Cα at only a few subsarcolemmal regions in resistance arteries. We have identified AKAP150 as the key protein, which targets protein kinase Cα to the L-type Ca channels and thereby enables its regulatory function. Accordingly, AKAP150 knockout mice (AKAP150) were found to lack persistent Ca sparklets and have lower arterial wall intracellular calcium ([Ca]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 Ca channel function is regulated by AKAP150-targeted protein kinase Cα signaling, which controls stuttering persistent Ca influx, vascular tone, and blood pressure under physiological conditions and underlies angiotensin II–dependent hypertension.