SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1−/- mice

Greenberg, HZE; Carlton-Carew, SRE; Zargaran, AK; Jahan, KS; Birnbaumer, L; Albert, AP (2019) Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1−/- mice. Channels, 13 (1). pp. 410-423. ISSN 1933-6950 https://doi.org/10.1080/19336950.2019.1673131
SGUL Authors: Albert, Anthony Paul

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution.

Download (2MB) | Preview

Abstract

We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit mesenteric arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in mesenteric arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone.

Item Type: Article
Additional Information: © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: 0299 Other Physical Sciences, Biochemistry & Molecular Biology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Channels
ISSN: 1933-6950
Dates:
DateEvent
11 October 2019Published
24 September 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/13/10/30021British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
BB/J007226/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/M018350/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
Z01-ES-101684National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
URI: https://openaccess.sgul.ac.uk/id/eprint/111281
Publisher's version: https://doi.org/10.1080/19336950.2019.1673131

Actions (login required)

Edit Item Edit Item