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Am J Physiol Heart Circ Physiol 295: H826-H834, 2008. First published June 20, 2008; doi:10.1152/ajpheart.01396.2007 Free Article
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Phospholipase C-{delta}1 modulates sustained contraction of rat mesenteric small arteries in response to noradrenaline, but not endothelin-1

Christopher J. Clarke, Simon Forman, James Pritchett, Vasken Ohanian, and Jacqueline Ohanian

Cardiovascular Research Group, School of Clinical and Laboratory Science, Core Technology Facility, University of Manchester, Manchester, United Kingdom

Submitted 3 December 2007 ; accepted in final form 16 June 2008

Vasoconstrictors activate phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), leading to calcium mobilization, protein kinase C activation, and contraction. Our aim was to investigate whether PLC-{delta}1, a PLC isoform implicated in {alpha}1-adrenoreceptor signaling and the pathogenesis of hypertension, is involved in noradrenaline (NA) or endothelin (ET-1)-induced PIP2 hydrolysis and contraction. Rat mesenteric small arteries were studied. Contractility was measured by pressure myography, phospholipids or inositol phosphates were measured by radiolabeling with 33Pi or myo-[3H]inositol, and caveolae/rafts were prepared by discontinuous sucrose density centrifugation. PLC-{delta}1 was localized by immunoblot analysis and neutralized by delivery of PLC-{delta}1 antibody. The PLC inhibitor U73122 [GenBank] , but not the negative control U-73342, markedly inhibited NA and ET-1 contraction but had no effect on potassium or phorbol ester contraction, implicating PLC activity in receptor-mediated smooth muscle contraction. PLC-{delta}1 was present in caveolae/rafts, and NA, but not ET-1, stimulated a rapid twofold increase in PLC-{delta}1 levels in these domains. PLC-{delta}1 is calcium dependent, and removal of extracellular calcium prevented its association with caveolae/rafts in response to NA, concomitantly reducing NA-induced [33P]PIP2 hydrolysis and [3H]inositol phosphate formation but with no effect on ET-1-induced [33P]PIP2 hydrolysis. Neutralization of PLC-{delta}1 by PLC-{delta}1 antibody prevented its caveolae/raft association and attenuated the sustained contractile response to NA compared with control antibodies. In contrast, ET-1-induced contraction was not affected by PLC-{delta}1 antibody. These results indicate the novel and selective role of caveolae/raft localized PLC-{delta}1 in NA-induced PIP2 hydrolysis and sustained contraction in intact vascular tissue.

signal transduction; vascular smooth muscle; phosphoinositide; caveolae; lipid rafts


Address for reprint requests and other correspondence: J. Ohanian, Cardiovascular Research Group, School of Clinical and Laboratory Science, Univ. of Manchester, Core Technology Facility (3rdfloor), 46 Grafton St., Manchester M13 9NT, UK (e-mail: johanian{at}manchester.ac.uk)






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