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ADP-ribosylation factor-dependent phospholipase D activation by the M-3 muscarinic receptor

Mitchell, R. and Robertson, D.N. and Holland, P.J. and Collins, D. and Lutz, E.M. and Johnson, M.S. (2003) ADP-ribosylation factor-dependent phospholipase D activation by the M-3 muscarinic receptor. Journal of Biological Chemistry, 278 (36). pp. 33818-33830. ISSN 0021-9258

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Abstract

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 Gq/11, phospholipase C, Ca2, 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.