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S1928 Phosphorylation Tunes Vascular L‐type Channel Ca V 1.2 and Arterial Function during Angiotensin II Signaling and Hypertension
Author(s) -
Flores Tamez Victor,
MartinAragón Baudel Miguel,
Le Thanhmai,
Syed Arslan,
Ramer Victoria,
Hell Johannes,
NievesCintrón Madeline,
Navedo Manuel
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01663
Subject(s) - endocrinology , angiotensin ii , vascular smooth muscle , medicine , mesenteric arteries , cav1.2 , phosphorylation , contractility , contraction (grammar) , chemistry , biology , blood pressure , microbiology and biotechnology , artery , voltage dependent calcium channel , smooth muscle , calcium
The L‐type channel Ca V 1.2 is essential for vascular smooth muscle contraction and arterial tone. Increased vascular Ca V 1.2 expression and function are related to high smooth muscle contractility and enhanced arterial tone during hypertension, which is characterized by enhanced angiotensin II (angII) signaling. Several pathways have been proposed to account for increased Ca V 1.2 expression during hypertension, including increased Ca V 1.2 trafficking. However, mechanisms underlying enhanced Ca V 1.2 function during angII signaling and hypertension remain a subject of intense investigation. In this study, we hypothesize that Ca V 1.2 phosphorylation at the S1928 site is a key event that mediates increased channel activity and vascular reactivity during angII signaling and hypertension. Initial experiments found increased S1928 phosphorylation in angII‐treated wild type arterial lysates. This was associated with elevated vascular smooth muscle whole‐cell L‐type channel currents, global intracellular Ca 2+ , and contraction. Similarly, ex vivo and in vivo experiments in mesenteric arteries reveal an increased arterial tone and decreased mesenteric blood flow from wild type mice. Moreover, smooth muscle cells treated with angII showed a redistribution of Ca V 1.2 into larger clusters. These functional changes were prevented or significantly ameliorated in arteries or cells from a knockin mouse expressing a mutant Ca V 1.2 in which serine was replaced with alanine at position 1928 (S1928A mouse) and by protein kinase C inhibition. In angII‐induced hypertensive mice, increased Ca V 1.2 clusters size and channel activity, enhanced arterial tone, and mean arterial pressure in wild type mice were prevented or significantly reduce in S1928A mice. Altogether, these results suggest a key role for phosphorylation of Ca V 1.2 at S1928 in regulating Ca V 1.2 distribution, activity, and vascular function during angII signaling and hypertension. Phosphorylation of this single vascular Ca V 1.2 amino acid could be an essential regulatory mechanism that could be exploited for therapeutic intervention.