α1 C S1928 Phosphorylation of Ca V 1.2 Channel Controls Vascular Reactivity and Blood Pressure.

Autor: Flores-Tamez VA; Department of Pharmacology University of California Davis Davis CA USA., Martín-Aragón Baudel M; Department of Pharmacology University of California Davis Davis CA USA., Hong J; Department of Pharmacology University of California Davis Davis CA USA., Taylor JL; Department of Pharmacology University of California Davis Davis CA USA., Ren L; Department of Pharmacology University of California Davis Davis CA USA., Le T; Department of Pharmacology University of California Davis Davis CA USA., Syed AU; Department of Pharmacology University of California Davis Davis CA USA., Moustafa Y; Department of Pharmacology University of California Davis Davis CA USA., Singhrao N; Department of Pharmacology University of California Davis Davis CA USA., Lemus-Martinez WR; Department of Pharmacology University of California Davis Davis CA USA., Reddy GR; Department of Pharmacology University of California Davis Davis CA USA., Ramer V; Department of Pharmacology University of California Davis Davis CA USA., Man KNM; Department of Pharmacology University of California Davis Davis CA USA., Bartels P; Department of Pharmacology University of California Davis Davis CA USA., Chen-Izu Y; Department of Pharmacology University of California Davis Davis CA USA., Chen CY; Department of Pharmacology University of California Davis Davis CA USA., Simo S; Department of Cell Biology & Human Anatomy University of California Davis Davis CA USA., Dickson EJ; Department of Physiology & Membrane Biology University of California Davis Davis CA USA., Morotti S; Department of Pharmacology University of California Davis Davis CA USA., Grandi E; Department of Pharmacology University of California Davis Davis CA USA., Santana LF; Department of Physiology & Membrane Biology University of California Davis Davis CA USA., Hell JW; Department of Pharmacology University of California Davis Davis CA USA., Horne MC; Department of Pharmacology University of California Davis Davis CA USA., Nieves-Cintrón M; Department of Pharmacology University of California Davis Davis CA USA., Navedo MF; Department of Pharmacology University of California Davis Davis CA USA.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2024 Oct 15; Vol. 13 (20), pp. e035375. Date of Electronic Publication: 2024 Oct 08.
DOI: 10.1161/JAHA.124.035375
Abstrakt: Background: Increased vascular Ca V 1.2 channel function causes enhanced arterial tone during hypertension. This is mediated by elevations in angiotensin II/protein kinase C signaling. Yet, the mechanisms underlying these changes are unclear. We hypothesize that α1 C phosphorylation at serine 1928 (S1928) is a key event mediating increased Ca V 1.2 channel function and vascular reactivity during angiotensin II signaling and hypertension.
Methods and Results: The hypothesis was examined in freshly isolated mesenteric arteries and arterial myocytes from control and angiotensin II-infused mice. Specific techniques include superresolution imaging, proximity ligation assay, patch-clamp electrophysiology, Ca 2+ imaging, pressure myography, laser speckle imaging, and blood pressure telemetry. Hierarchical "nested" and appropriate parametric or nonparametric t test and ANOVAs were used to assess statistical differences. We found that angiotensin II redistributed the Ca V 1.2 pore-forming α1 C subunit into larger clusters. This was correlated with elevated Ca V 1.2 channel activity and cooperativity, global intracellular Ca 2+ and contraction of arterial myocytes, enhanced myogenic tone, and altered blood flow in wild-type mice. These angiotensin II-induced changes were prevented/ameliorated in cells/arteries from S1928 mutated to alanine knockin mice, which contain a negative modulation of the α1 C S1928 phosphorylation site. In angiotensin II-induced hypertension, increased α1 C clustering, Ca V 1.2 activity and cooperativity, myogenic tone, and blood pressure in wild-type cells/tissue/mice were averted/reduced in S1928 mutated to alanine samples.
Conclusions: Results suggest an essential role for α1 C S1928 phosphorylation in regulating channel distribution, activity and gating modality, and vascular function during angiotensin II signaling and hypertension. Phosphorylation of this single vascular α1 C amino acid could be a risk factor for hypertension that may be targeted for therapeutic intervention.
Databáze: MEDLINE
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