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Baldwin, Samuel N., Forrester, Elizabeth A., Homer, Natalie Z. M., Andrew, Ruth, Barrese, Vincenzo, Stott, Jennifer B., Isakson, Brant E., Albert, Anthony P. 
ORCID: https://orcid.org/0000-0002-3596-9634 and Greenwood, Iain A.
(2023)
Marked oestrous cycle-dependent regulation of rat arterial KV7.4 channels driven by GPER1.
British Journal of Pharmacology, 180 (2).
pp. 174-193.
ISSN 0007-1188
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Abstract
Background and Purpose: Kcnq-encoded KV7 channels (termed KV7.1–5) 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 KV7 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 KV7.4 channels in association with G-protein-coupled oestrogen receptor 1 (GPER1). Key Results: The KV7.2–5 activators S-1 and ML213 and the pan-KV7 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 KV7.4 but not KV7.1, KV7.5 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 KV7.4 encoded currents and ML213 relaxations and reduced the membrane abundance of KV7.4 and interaction between KV7.4 and heat shock protein 90 (HSP90), in arteries from F-D/M but not F-P/E. Conclusions and Implications: GPER1 signalling decreased KV7.4 membrane abundance in conjunction with diminished interaction with HSP90, giving rise to a ‘pro-contractile state’.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: SNB was funded by the British Heart Foundation (Grant #FS/18/41/33762) awarded to IAG. |
| Uncontrolled Keywords: | pharmacology ,/dk/atira/pure/subjectarea/asjc/3000/3004 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 01 Nov 2024 16:30 |
| Last Modified: | 07 Dec 2024 01:39 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97433 |
| DOI: | 10.1111/bph.15947 |
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