title: Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins.
abstract: mGlu7 receptors are coupled to Gi/Go-proteins and activate multiple transduction pathways, including inhibition of adenylyl cyclase activity and stimulation of ERK1/2 and JNK pathways. mGlu7 receptors play an important role in cognition and emotion and are involved in stress-related disorders such as anxiety and depression and in susceptibility to convulsive seizures. In spite of these potential clinical implications, little is known on the mechanisms that regulate mGlu7-receptor signaling. Here we show that mGlu7 receptor-dependent signaling pathways were regulated in a complementary manner by different GRK subtypes, with GRK4 affecting the adenylyl cyclase and the JNK pathways, and GRK2 selectively affecting the ERK1/2 pathway. Additionally we found that the two isoforms of non-visual arrestins, i.e. β-arrestin1 and β-arrestin2, exerted opposite effects on mGlu7-receptor signaling, with β-arrestin1 positively modulating ERK1/2 and inhibiting JNK, and β-arrestin2 doing the opposite. This represents a remarkable example of "reciprocal regulation" of receptor signaling by the two isoforms of β-arrestin. Finally we found that β-arrestin1 amplified mGlu7 receptor-dependent ERK1/2 activation in response to L-AP4 (an orthosteric agonist), but not in response to AMN082 (an atypical mGlu7-receptor allosteric agonist). The different effect of β-arrestin1 on L-AP4- and AMN082-stimulated ERK1/2 phosphorylation is in line with the emerging concept of β-arrestin-biased agonists. The present study may open new perspectives in elucidating the physio-pathological roles of the mGlu7 receptor and may provide new insights for the possibility to develop specific (biased) agonists that can selectively activate different signaling pathways.
authors.affiliation: Department of Physiology and Pharmacology "Vittorio Erspamer", University of Rome "Sapienza", P.le Aldo Moro, 5, 00185 Rome, Italy. Electronic address: luisa.iacovelli@uniroma1.it.
authors.forename: L
authors.initials: L
authors.lastname: Iacovelli
authors.affiliation: IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Felicioni
authors.affiliation: Department of Physiology and Pharmacology "Vittorio Erspamer", University of Rome "Sapienza", P.le Aldo Moro, 5, 00185 Rome, Italy; IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Department of Physiology and Pharmacology "Vittorio Erspamer", University of Rome "Sapienza", P.le Aldo Moro, 5, 00185 Rome, Italy; I.N.M. Neuromed, Località Camerelle, Pozzilli, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Dept. of Molecular Medicine, University of Rome "Sapienza", V.le Regina Elena 291, 00185 Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Blasi
mesh_terms: D000613:Aminobutyrates / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000613:Aminobutyrates; D019390:Arrestins; D001559:Benzhydryl Compounds; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D054768:G-Protein-Coupled Receptor Kinases; C012729:2-amino-4-phosphonobutyric acid
keywords: Arrestins; C-terminal domain of GRK2; FSK; G protein-coupled receptor; G protein-coupled receptor kinase; GPCR; GRK; GRK2-Cter; GRK2-K220R; JNK; Jun kinases; L-AP4; MAP kinases; MAPK; Signaling regulation; c-Jun N-terminal kinase; forskolin; kinase-dead GRK2 mutant; l-2-amino-4-phosphonobutanoate; mGlu; mGlu7 receptors; metabotropic glutamate receptor; mytogen activated protein kinases