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Shi, J., Ju, M., Large, W. A. and Albert, A. P. 
ORCID: https://orcid.org/0000-0002-3596-9634
(2012)
Pharmacological profile of phosphatidylinositol 3-kinases and related phosphatidylinositols mediating endothelinA receptor-operated native TRPC channels in rabbit coronary artery myocytes.
British Journal of Pharmacology, 166 (7).
pp. 2161-2175.
ISSN 0007-1188
Abstract
BACKGROUND AND PURPOSE EndothelinA (ETA) receptor-operated canonical transient receptor potential (TRPC) channels mediate Ca2+ influx pathways, which are important in coronary artery function. Biochemical pathways linking ETA receptor stimulation to TRPC channel opening are unknown. We investigated the involvement of phosphatidylinositol 3-kinases (PI3K) in ETA receptor activation of native heteromeric TRPC1/C5/C6 and TRPC3/C7 channels in rabbit coronary artery vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH A pharmacological profile of PI3K was created by studying the effect of pan-PI3K, pan-Class I PI3K and Class I PI3K isoform-selective inhibitors on ETA receptor-evoked single TRPC1/C5/C6 and TRPC3/C7 channel activities in cell-attached patches from rabbit freshly isolated coronary artery VSMCs. The action of phosphatidylinositol 3-phosphate- [PI(3)P], 4-phosphate- [PI(4)P] and 5-phosphate- [PI(5)P] containing molecules involved in PI3K-mediated reactions were studied in inside-out patches. Expression of PI3K family members in coronary artery tissue lysates were analysed using quantitative PCR. KEY RESULTS ETA receptor-operated TRPC1/C5/C6 and TRPC3/C7 channel activities were inhibited by wortmannin. However, ZSTK474 and AS252424 reduced ET A receptor-evoked TRPC1/C5/C6 channel activity but potentiated TRPC3/C7 channel activity. All the PI(3)P-, PI(4)P- and PI(5)P-containing molecules tested induced TRPC1/C5/C6 channel activation, whereas only PI(3)P stimulated TRPC3/C7 channels. CONCLUSIONS AND IMPLICATIONS ETA receptor-operated native TRPC1/C5/C6 and TRPC3/C7 channel activities are likely to be mediated by Class I PI3KΥ and Class II/III PI3K isoforms, respectively. ETA receptor-evoked and constitutively active PI3KΥ-mediated pathways inhibit TRPC3/C7 channel activation. PI3K-mediated pathways are novel regulators of native TRPC channels in VSMCs, and these signalling cascades are potential pharmacological targets for coronary artery disease.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | canonical transient receptor potential,endothelin,phosphatidylinositol,phosphatidylinositol 3-kinase,vascular smooth muscle,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: | 29 Oct 2024 09:30 |
| Last Modified: | 03 Nov 2024 07:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97257 |
| DOI: | 10.1111/j.1476-5381.2012.01937.x |
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