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• W1570755321 abstract "BACKGROUND AND PURPOSE Endothelin A (ET A ) receptor‐operated canonical transient receptor potential (TRPC) channels mediate Ca 2+ influx pathways, which are important in coronary artery function. Biochemical pathways linking ET A receptor stimulation to TRPC channel opening are unknown. We investigated the involvement of phosphatidylinositol 3‐kinases (PI3K) in ET A 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 ET A 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 ET A 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 ET A receptor‐operated native TRPC1/C5/C6 and TRPC3/C7 channel activities are likely to be mediated by Class I PI3Kγ and Class II/III PI3K isoforms, respectively. ET A receptor‐evoked and constitutively active PI3Kγ‐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." @default.
• W1570755321 created "2016-06-24" @default.
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• W1570755321 date "2012-07-09" @default.
• W1570755321 modified "2023-10-18" @default.
• W1570755321 title "Pharmacological profile of phosphatidylinositol 3-kinases and related phosphatidylinositols mediating endothelinA receptor-operated native TRPC channels in rabbit coronary artery myocytes" @default.
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• W1570755321 doi "https://doi.org/10.1111/j.1476-5381.2012.01937.x" @default.
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