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α1C S1928 Phosphorylation of CaV1.2 Channel Controls Vascular Reactivity and Blood Pressure

Victor A Flores-Tamez1, Miguel Martín-Aragón Baudel1, Junyoung Hong1

  • 1Department of Pharmacology University of California Davis Davis CA USA.

Journal of the American Heart Association
|October 8, 2024
PubMed

Insights

Phosphorylation of the alpha1C subunit at serine 1928 is key to increased vascular CaV1.2 channel function in hypertension. Blocking this phosphorylation reduces channel activity and lowers blood pressure.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Hypertension Research

Background:

  • Vascular CaV1.2 channel function is elevated in hypertension, driven by angiotensin II and protein kinase C signaling.
  • The precise mechanisms linking these signaling pathways to altered channel function remain unclear.
  • This study investigates the role of alpha1C subunit phosphorylation at serine 1928 (S1928) in mediating these changes.

Purpose of the Study:

  • To determine if alpha1C S1928 phosphorylation is a critical event in enhancing CaV1.2 channel function and vascular reactivity.
  • To elucidate the impact of angiotensin II signaling on CaV1.2 channel distribution and activity.
  • To assess the therapeutic potential of targeting alpha1C S1928 phosphorylation in hypertension.

Main Methods:

  • Utilized freshly isolated mesenteric arteries and arterial myocytes from control and angiotensin II-infused mice.
  • Employed superresolution imaging, proximity ligation assay, patch-clamp electrophysiology, Ca2+ imaging, pressure myography, laser speckle imaging, and blood pressure telemetry.
  • Compared wild-type mice with S1928 mutated to alanine knockin mice to assess the functional significance of S1928 phosphorylation.

Main Results:

  • Angiotensin II increased CaV1.2 alpha1C subunit clustering, correlating with elevated channel activity, myocyte contraction, myogenic tone, and altered blood flow.
  • These angiotensin II-induced effects were prevented or reduced in S1928 mutated to alanine mice.
  • In angiotensin II-induced hypertension, increased alpha1C clustering, channel activity, myogenic tone, and blood pressure were averted or reduced in S1928 mutated to alanine samples.

Conclusions:

  • Alpha1C S1928 phosphorylation plays an essential role in regulating CaV1.2 channel distribution, activity, and gating.
  • This phosphorylation event is crucial for vascular function during angiotensin II signaling and hypertension.
  • Targeting alpha1C S1928 phosphorylation may offer a novel therapeutic strategy for hypertension.
Abstract

Keywords:
cardiovascularclusteringcooperativitydiabeteshypertension

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