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J. Biol. Chem., Vol. 278, Issue 36, 33818-33830, September 5, 2003

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ADP-ribosylation Factor-dependent Phospholipase D Activation by the M₃ Muscarinic Receptor^*

Rory Mitchell  , Derek N. Robertson , Pamela J. Holland , Daniel Collins , Eve M. Lutz ¶ and Melanie S. Johnson 

From the Medical Research Council Membrane and Adapter Proteins Co-operative Group, Membrane Biology Interdisciplinary Research Group, School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, United Kingdom and the ^¶Department of Bioscience, University of Strathclyde, George Street, Glasgow G1 1XW, United Kingdom

G protein-coupled receptors can potentially activate phospholipase D (PLD) by a number of routes. We show here that the native M₃ muscarinic receptor in 1321N1 cells and an epitope-tagged M₃ receptor expressed in COS7 cells substantially utilize an ADP-ribosylation factor (ARF)-dependent route of PLD activation. This pathway is activated at the plasma membrane but appears to be largely independent of G, phospholipase C, Ca²⁺ q/11, protein kinase C, tyrosine kinases, and phosphatidyl inositol 3-kinase. We report instead that it involves physical association of ARF with the M₃ receptor as demonstrated by co-immunoprecipitation and by in vitro interaction with a glutathione S-transferase fusion protein of the receptor's third intracellular loop domain. Experiments with mutant constructs of ARF1/6 and PLD1/2 indicate that the M₃ receptor displays a major ARF1-dependent route of PLD1 activation with an additional ARF6-dependent pathway to PLD1 or PLD2. Examples of other G protein-coupled receptors assessed in comparison display alternative pathways of protein kinase C- or ARF6-dependent activation of PLD2.

Received for publication, June 3, 2003

^* This work was supported by grants from the Medical Research Council (United Kingdom) (to R. M.). 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.: 44131-650-3550/2; Fax: 44131-650-6527; E-mail: Rory.Mitchell{at}ed.ac.uk.

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