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J. Biol. Chem., Vol. 280, Issue 35, 30705-30711, September 2, 2005

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Disruption of Lipid Rafts Inhibits P2X₁ Receptor-mediated Currents and Arterial Vasoconstriction^*

Catherine Vial and Richard J. Evans

From the Department of Cell Physiology & Pharmacology, University of Leicester, Leicester, LE1 9HN United Kingdom

P2X₁ receptors for ATP are ligand-gated cation channels expressed on a range of smooth muscle preparations and blood platelets. The receptors appear to be clustered close to sympathetic nerve varicosities and mediate the underlying membrane potential changes and constriction following nerve stimulation in a range of arteries and resistance arterioles. In this study we have used discontinuous sucrose density gradients, Western blot analysis, and cholesterol measurements to show that recombinant and smooth muscle (rat tail artery, vas deferens, and bladder) P2X₁ receptors are present in cholesterol-rich lipid rafts and co-localize with the lipid raft markers flotillin-1 and -2. Lipid rafts are specialized lipid membrane microdomains involved in signaling and trafficking. To determine whether lipid raft association was essential for P2X₁ receptor channel function we used the cholesterol-depleting agent methyl--cyclodextrin (10 mM for 1 h). This led to a redistribution of the P2X₁ receptor throughout the sucrose gradient and reduced P2X₁ receptor-mediated (,-methylene ATP, 10 µM) currents in HEK293 cells by >90% and contractions of the rat tail artery by 50%. However contractions evoked by potassium chloride (60 mM) were unaffected by methyl--cyclodextrin and the inactive analogue -cyclodextrin had no effect on P2X₁ receptor-mediated currents or contractions. P2X₁ receptors are subject to ongoing regulation by receptors and kinases, and the present results suggest that lipid rafts are an essential component in the maintenance of these localized signaling domains and play an important role in P2X₁ receptor-mediated control of arteries.

Received for publication, April 19, 2005 , and in revised form, June 21, 2005.

^* This work was supported by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44-116-252-3032; Fax: 44-116-252-5045; E-mail: rje6{at}le.ac.uk.

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