Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins
Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins
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DOI：
10.1016/j.neuropharm.2013.10.013
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发表时间：
2014-02-01
影响因子：
4.7
通讯作者：
De Blasi, A.
中科院分区：
文献类型：
--
作者：
Lacovelli, L.;Felicioni, M.;De Blasi, A.
mGlu7受体与Gi/ go蛋白偶联并激活多种转导途径，包括抑制腺苷酸环化酶活性和刺激ERK1/2和JNK途径。mGlu7受体在认知和情绪中发挥重要作用，并参与焦虑和抑郁等压力相关疾病以及对惊厥发作的易感性。尽管有这些潜在的临床意义，但对调控mg177受体信号传导的机制知之甚少。本研究表明，mGlu7受体依赖的信号通路受到不同GRK亚型的互补调节，其中GRK4影响腺苷酸环化酶和JNK途径，GRK2选择性地影响ERK1/2途径。此外，我们发现非视觉抑制蛋白的两种同工型，即β -arrestin2和β -arrestin2，对mg17受体信号传导产生相反的影响，β -arrestin1正调节ERK1/2并抑制JNK，而β -arrestin2则相反。最后，我们发现β -arrestin1在L-AP4（一种正构激动剂）的作用下可扩增mg177受体依赖性ERK1/2的激活，但在AMN082（一种非典型mg177受体变构激动剂）的作用下则不能扩增。β -arrestinl对L-AP4-和amn082刺激的ERK1/2磷酸化的不同影响与β - arrestinn偏向激动剂的新兴概念一致。本研究可能为阐明mG1u7受体的生理病理作用开辟新的视角，并可能为开发能够选择性激活不同信号通路的特异性（偏倚）激动剂提供新的见解。(C) 2013 Elsevier Ltd.版权所有。
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.