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 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 Calpha at only a few subsarcolemmal regions in resistance arteries. We have identified AKAP150 as the key protein, which targets protein kinase Calpha 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.
Navedo
Manuel F
MF
Department of Physiology & Biophysics, University of Washington, Seattle, WA 98195, USA.
Nieves-Cintrón
Madeline
M
Amberg
Gregory C
GC
Yuan
Can
C
Votaw
V Scott
VS
Lederer
W Jonathan
WJ
McKnight
G Stanley
GS
Santana
Luis F
LF
D054758:A Kinase Anchor Proteins / Q000172:deficiency / Q000502:physiology*; D000804:Angiotensin II; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D006973:Hypertension / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D051571:Protein Kinase C-alpha / Q000378:metabolism; D014655:Vascular Resistance
D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D020746:Calcium Channels, L-Type; D000804:Angiotensin II; D051571:Protein Kinase C-alpha