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Differential effects of PI3K isoforms on TRPC channels in vascular smooth muscle: Novel actions of PI(3)P‐containing molecules
Author(s) -
Albert Anthony Paul,
Shi Jian,
Ju Min,
Large William
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1048.16
Subject(s) - trpc , trpc3 , trpc1 , transient receptor potential channel , phospholipase c , microbiology and biotechnology , wortmannin , chemistry , trpc5 , vascular smooth muscle , receptor , signal transduction , medicine , phosphatidylinositol , endocrinology , biology , biochemistry , smooth muscle
It is thought that G‐protein‐coupled receptors linked to phospholipase‐mediated pathways and generation of diacylglycerol (DAG) activate TRPC1 and TRPC3/C6/C7 channel subtypes in vascular smooth muscle cells (VSMCs), via respectively PKC‐dependent and –independent mechanisms. However, endothelinA receptor (ETA) stimulation of TRPC1/C5/C6 and TRPC3/C7 channel activities in rabbit coronary artery VSMCs are not blocked by phospholipase inhibitors. The aim of this work was to study activation mechanisms of these ETA receptor‐induced TRPC channels using patch clamp techniques. ETA receptor‐evoked TRPC1/C5/C6 and TRPC3/C7 channel activities were both inhibited by low concentrations of wortmannin. In addition, TRPC1/C5/C6 channel activity was inhibited by the pan‐Class I PI3K isoform inhibitor ZSTK474, and the Class I PI3Kgamma isoform‐selective inhibitor AS252424. Interestingly, ZSTK474 and AS252424 both increased ETA receptor‐evoked TRPC3/C7 channel activity. Substrates and products of PI3K‐mediated pathways activated TRPC1/C5/C6 channels. In contrast, only PI(3)P activated TRPC3/C7 channels, whereas substrates and other products of PI3K‐mediated processes inhibited these channels. These results show for the first time that PI3K‐mediated signalling pathways have a pivotal role in regulating native TRPC channels in VSMCs. This work was supported by the British Heart Foundation.