Rhodopsin-family receptors associate with small G proteins to activate phospholipase D

Nature. 1998 Mar 26;392(6674):411-4. doi: 10.1038/32937.


G-protein-coupled receptors of the rhodopsin family transduce many important neural and endocrine signals. These receptors activate heterotrimeric G proteins and in many cases also cause activation of phospholipase D, an enzyme that can be controlled by the small G proteins ARF and RhoA. Here we show that the activation of phospholipase D that is induced by many, but not all, Ca2+-mobilizing G-protein-coupled receptors is sensitive to inhibitors of ARF and of RhoA. Receptors of this type were co-immunoprecipitated with ARF or RhoA on exposure to agonists, and the effects of GTP analogues on ligand binding to the receptor changed to a profile that is characteristic of small G proteins. These receptors contain the amino-acid sequence AsnProXXTyr in their seventh transmembrane domain, whereas receptors capable of activating phospholipase D without involving ARF contain the sequence AspProXXTyr. Mutation of this latter sequence to AsnProXXTyr in the gonadotropin-releasing hormone receptor conferred sensitivity to an inhibitor of ARF, and the reciprocal mutation in the 5-HT2A receptor for 5-hydroxy-tryptamine reduced its sensitivity to the inhibitor. Receptors carrying the AsnProXXTyr motif thus seem to form functional complexes with ARF and RhoA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP-Ribosylation Factors
  • Animals
  • Brefeldin A
  • COS Cells
  • Cyclopentanes / pharmacology
  • Enzyme Activation
  • Estrenes / pharmacology
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / metabolism*
  • Guanosine Triphosphate / analogs & derivatives
  • Guanosine Triphosphate / metabolism
  • Humans
  • Male
  • Phospholipase D / antagonists & inhibitors
  • Phospholipase D / metabolism*
  • Pyrrolidinones / pharmacology
  • Rats
  • Receptor, Muscarinic M3
  • Receptors, LHRH / agonists
  • Receptors, LHRH / chemistry
  • Receptors, LHRH / genetics
  • Receptors, LHRH / metabolism*
  • Receptors, Muscarinic / chemistry
  • Receptors, Muscarinic / metabolism*
  • Recombinant Proteins / metabolism
  • Rhodopsin / chemistry
  • Rhodopsin / metabolism*
  • Tumor Cells, Cultured
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism
  • rhoA GTP-Binding Protein


  • Cyclopentanes
  • Estrenes
  • Pyrrolidinones
  • Receptor, Muscarinic M3
  • Receptors, LHRH
  • Receptors, Muscarinic
  • Recombinant Proteins
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Brefeldin A
  • Guanosine Triphosphate
  • Rhodopsin
  • Type C Phospholipases
  • Phospholipase D
  • GTP-Binding Proteins
  • ADP-Ribosylation Factors
  • rhoA GTP-Binding Protein