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Translocation of PKG1α acts on TRPV4-C1 heteromeric channels to inhibit endothelial Ca(2+) entry

Peng Zhang1, Ai-Qin Mao1, Chun-Yuan Sun1

  • 1School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.

Acta Pharmacologica Sinica
|July 12, 2016
PubMed

Insights

PKG1α negatively regulates TRPV4-TRPC1 channels in endothelial cells. This involves increased proximity and phosphorylation of TRPC1, leading to reduced calcium entry and vascular relaxation.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Ion Channel Physiology

Background:

  • TRPV4-TRPC1 heteromeric channels are crucial for store-operated calcium entry in vascular endothelial cells.
  • The negative regulation of these channels is not fully understood, representing a gap in knowledge.

Purpose of the Study:

  • To investigate the inhibitory effect of Protein Kinase G type 1-alpha (PKG1α) on TRPV4-TRPC1 heteromeric channels.
  • To elucidate the molecular mechanisms underlying PKG1α-mediated channel regulation.

Main Methods:

  • Immuno-fluorescence resonance energy transfer (FRET) to assess PKG1α and TRPC1 spatial proximity.
  • Phosphorylation assays to determine TRPC1 phosphorylation sites.
  • [Ca(2+)]i transients and cation currents measured in MAECs.
  • Wire myography used to evaluate vascular relaxation in rat mesenteric arteries.

Main Results:

  • PKG1α translocates to the plasma membrane and increases proximity to TRPC1 upon stimulation.
  • PKG directly phosphorylates TRPC1 at Ser172 and Thr313 residues.
  • PKG activation significantly reduces calcium transients, cation currents, and vascular relaxation.

Conclusions:

  • PKG1α negatively regulates endothelial TRPV4-TRPC1 channels.
  • This regulation occurs via enhanced PKG1α-TRPC1 spatial proximity and TRPC1 phosphorylation at specific sites.
  • This mechanism contributes to the control of vascular tone.
Abstract

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