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

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 mG1u7-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. beta-arrestin2 and beta-arrestin2, exerted opposite effects on mG1u7-receptor signaling, with beta-arrestin1 positively modulating ERK1/2 and inhibiting JNK, and beta-arrestin2 doing the opposite. This represents a remarkable example of "reciprocal regulation" of receptor signaling by the two isoforms of beta-arrestin1 Finally we found that (beta-arrestin1 amplified mG1u7 receptor-dependent ERK1/2 activation in response to L-AP4 (an orthosteric agonist), but not in response to AMN082 (an atypical mG1u7-receptor allosteric agonist). The different effect of beta-arrestinl on L-AP4- and AMN082-stimulated ERK1/2 phosphorylation is in line with the emerging concept of beta-arrestin-biased agonists. The present study may open new perspectives in elucidating the physio-pathological roles of the mG1u7 receptor and may provide new insights for the possibility to develop specific (biased) agonists that can selectively activate different signaling pathways. (C) 2013 Elsevier Ltd. All rights reserved.