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Vol. 59, Issue 6, 1523-1532, June 2001

ADP-Ribosylation Factor-Dependent Phospholipase D Activation by VPAC Receptors and a PAC1 Receptor Splice Variant

Derek A. McCulloch,1 Eve M. Lutz,2 Melanie S. Johnson, Derek N. Robertson, Chris J. MacKenzie,3 Pamela J. Holland, and Rory Mitchell

Medical Research Council Membrane and Adapter Proteins Co-operative Group, Membrane Biology Group, Department of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, United Kingdom

The VPAC1 and VPAC2 receptors for vasoactive intestinal polypeptide and the PAC1 receptor for pituitary adenylate cyclase-activating polypeptide are members of a subfamily of G protein-coupled receptors (GPCRs). We recently reported that phospholipase D (PLD) activation by members of the rhodopsin group of GPCRs occurs by at least two routes, one of which seems to involve the small G protein ADP-ribosylation factor (ARF) and its physical association with GPCRs. Here we report that rat VPAC and PAC1 receptors can also stimulate PLD (albeit less potently than adenylate cyclase) in transfected cells and also in cells where they are natively expressed. PLD responses of the VPAC receptors and the hop1 spice variant of the PAC1 receptor but not its null form are sensitive to brefeldin A (BFA), an inhibitor of GTP exchange at ARF. The presence of the hop1 cassette in the rat PAC1 receptor facilitates PLD activation in the absence of marked changes in ligand binding, receptor internalization, and adenylate cyclase activation, with some reduction in phospholipase C activation. Both VPAC2 and PAC1-hop1 (but not PAC1-null) receptors were shown to associate with immunoprecipitates directed against native or epitope-tagged ARF. A chimeric construct of the VPAC2 receptor body with intracellular loop 3 (i3) of the PAC1-null receptor mediated BFA-insensitive activation of PLD, whereas the response of the corresponding PAC1-hop1 construct was BFA-sensitive. Motifs in i3 of the PAC1-hop1 receptor may act as critical determinants of coupling to ARF-dependent PLD activation by contributing to the GPCR:ARF interface.

1 Present address: Kennedy Institute of Rheumatology, 1 Aspenlea Rd., Hammersmith, London, UK.

2 Present address: Department of Bioscience and Biotechnology, University of Strathclyde, Glasgow, UK.

3 Present address: Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, UK.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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