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.

Iacovelli, L., Felicioni, M., NISTICO', R.G., Nicoletti, F., & De Blasi, A. (2013). Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins. NEUROPHARMACOLOGY, 77, 303-312 [10.1016/j.neuropharm.2013.10.013].

Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins

NISTICO', ROBERT GIOVANNI;
2013

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14
English
Con Impact Factor ISI
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; Aminobutyrates; Arrestins; Benzhydryl Compounds; G-Protein-Coupled Receptor Kinases; HEK293 Cells; Humans; Phosphorylation; Receptors, Metabotropic Glutamate; Signal Transduction
Iacovelli, L., Felicioni, M., NISTICO', R.G., Nicoletti, F., & De Blasi, A. (2013). Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins. NEUROPHARMACOLOGY, 77, 303-312 [10.1016/j.neuropharm.2013.10.013].
Iacovelli, L; Felicioni, M; Nistico', Rg; Nicoletti, F; De Blasi, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/133145
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