Abstract

It is generally accepted that TRPC3/C6 and C7 cation channel proteins are activated by diacylglycerol (DAG) via a protein kinase C (PKC) independent pathway but there is no clear evidence on how this DAG‐ mediated process occurs. However a precursor of DAG, phosphatidylinositol‐4, 5‐bisphosphate (PIP2), may also have an important role in modulating the activity of different TRP channels (Voets & Nilius, 2007). We have shown in native rabbit mesenteric arteries that angiotensin II (Ang II) activates a channel, which TRPC6 proteins are likely to represent essential molecular components, through DAG acting via a PKC‐independent mechanism (Saleh et al, 2006) and the present work investigates the effect of PIP2 on this channel activity using whole‐cell and single channel recording.Inclusion of PIP2 in the patch pipette solution and application of PIP2 to the cytosolic surface of inside‐out patches markedly reduced Ang II‐induced whole‐cell cation conductances and channel activity by over 80% at −50 mV. Moreover application of an anti‐PIP2 antibody increased TRPC6 channel activity induced by either Ang II or OAG in inside‐out patches. In cell‐attached patches bath application of the phosphatidylinositol kinase inhibitors wortmannin and LY294002 and the PIP2 scavenger poly‐lysine produced pronounced activation of TRPC6 channel activity.These novel data indicate that PIP2, a substrate of DAG production, has a profound inhibitory action of TRPC6 channel activity in native arterial myocytes indicating that both hydrolysis of PIP2 and production of DAG may be important in activating channels from the TRPC3/C6/C7 subfamily of TRPC proteins.Saleh SN et al (2006). J Physiol 577, 479–495. Voets T & Nilius B (2007). J Physiol 582, 939–944. Work supported by The Wellcome Trust.

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