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

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalCirculation Research
Volume102
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

Keywords

  • L-type Ca channels
  • Myogenic tone
  • Protein kinase C
  • Total internal reflection fluorescence microscopy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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