Baldwin, SN; Forrester, EA; Homer, NZM; Andrew, R; Barrese, V; Stott, JB; Isakson, BE; Albert, AP; Greenwood, IA
(2022)
Marked oestrous cycle-dependent regulation of rat arterial KV 7.4 channels driven by GPER1.
Br J Pharmacol, 180 (2).
pp. 174-193.
ISSN 1476-5381
https://doi.org/10.1111/bph.15947
SGUL Authors: Albert, Anthony Paul Greenwood, Iain Andrew Stott, Jennifer Beth
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Abstract
BACKGROUND AND PURPOSE: Kcnq-encoded KV 7 channels (termed KV 7.1-5) regulate vascular smooth muscle cell (VSMC) contractility at rest and as targets of receptor-mediated responses. However, the current data are mostly derived from males. Considering the known effects of sex, the oestrous cycle and sex hormones on vascular reactivity, here we have characterised the molecular and functional properties of KV 7 channels from renal and mesenteric arteries from female Wistar rats separated into di-oestrus and met-oestrus (F-D/M) and pro-oestrus and oestrus (F-P/E). EXPERIMENTAL APPROACH: RT-qPCR, immunocytochemistry, proximity ligation assay and wire myography were performed in renal and mesenteric arteries. Circulating sex hormone concentrations were determined by liquid chromatography-tandem mass spectrometry. Whole-cell electrophysiology was undertaken on cells expressing KV 7.4 channels in association with G-protein-coupled oestrogen receptor 1 (GPER1). KEY RESULTS: The KV 7.2-5 activators S-1 and ML213 and the pan-KV 7 inhibitor linopirdine were more effective in arteries from F-D/M compared with F-P/E animals. In VSMCs isolated from F-P/E rats, exploratory evidence indicates reduced membrane abundance of KV 7.4 but not KV 7.1, KV 7.5 and Kcne4 when compared with cells from F-D/M. Plasma oestradiol was higher in F-P/E compared with F-D/M, and progesterone showed the converse pattern. Oestradiol/GPER1 agonist G-1 diminished KV 7.4 encoded currents and ML213 relaxations and reduced the membrane abundance of KV 7.4 and interaction between KV 7.4 and heat shock protein 90 (HSP90), in arteries from F-D/M but not F-P/E. CONCLUSIONS AND IMPLICATIONS: GPER1 signalling decreased KV 7.4 membrane abundance in conjunction with diminished interaction with HSP90, giving rise to a 'pro-contractile state'.
Item Type: | Article | ||||||||
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Additional Information: | © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | ||||||||
Keywords: | 1115 Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Institute of Medical & Biomedical Education (IMBE) Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
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Journal or Publication Title: | Br J Pharmacol | ||||||||
ISSN: | 1476-5381 | ||||||||
Language: | eng | ||||||||
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||||
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PubMed ID: | 36085551 | ||||||||
Web of Science ID: | WOS:000852987800189 | ||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/114864 | ||||||||
Publisher's version: | https://doi.org/10.1111/bph.15947 |
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