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Regulation of mGlu4 Metabotropic Glutamate Receptor Signaling by Type-2 G-Protein Coupled Receptor Kinase (GRK2)

Department of Human Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy (L.I., M.I., V.D.G.G., D.M., F.N.); I.N.M. Neuromed, Pozzilli, Italy (L.I., L.C., A.P., F.N., A.D.B.); and Institute of Experimental Medicine Czech Academy of Science, Prague, Czech Republic (J.B.)

We examined the role of G-protein coupled receptor kinase-2 (GRK2) in the homologous desensitization of mGlu4 metabotropic glutamate receptors transiently expressed in human embryonic kidney (HEK) 293 cells. Receptor activation with the agonist L-2-amino-4-phosphonobutanoate (L-AP4) stimulated at least two distinct signaling pathways: inhibition of cAMP formation and activation of the mitogen-activated protein kinase (MAPK) pathway [assessed by Western blot analysis of phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2]. Activation of both pathways was attenuated by pertussis toxin. Overexpression of GRK2 (but not GRK4) largely attenuated the stimulation of the MAPK pathway by L-AP4, whereas it slightly potentiated the inhibition of FSK-stimulated cAMP formation. Transfection with a kinase-dead mutant of GRK2 (GRK2-K220R) or with the C-terminal fragment of GRK2 also reduced the mGlu4-mediated stimulation of MAPK, suggesting that GRK2 binds to the G subunits to inhibit signal propagation toward the MAPK pathway. This was confirmed by the evidence that GRK2 coimmunoprecipitated with G subunits in an agonist-dependent manner. Finally, neither GRK2 nor its kinase-dead mutant had any effect on agonist-induced mGlu4 receptor internalization in HEK293 cells transiently transfected with GFP-tagged receptors. Agonist-dependent internalization was instead abolished by a negative-dominant mutant of dynamin, which also reduced the stimulation of MAPK pathway by L-AP4. We speculate that GRK2 acts as a "switch molecule" by inhibiting the mGlu4 receptor-mediated stimulation of MAPK and therefore directing the signal propagation toward the inhibition of adenylyl cyclase.

Received August 4, 2003; accepted January 29, 2004.

Address correspondence to: Luisa Iacovelli PhD, Dept. of Human Physiology and Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro, 6, 00185, Rome Italy. E-mail: luisa.iacovelli{at}uniroma1.it

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