Pael receptor is involved in dopamine metabolism in the nigrostriatal system

Imai, Yuzuru; Inoue, Haruhisa; Kataoka, Ayane; Wang, Hua‐Qin; Masuda, Masao; Ikeda, Toshio; Tsukita, Kayoko; Soda, Mitsuhiro; Kodama, Tohru; Fuwa, Tatsu; Honda, Yoshiaki; Kaneko, Satoshi; Matsumoto, Sadayuki; Wakamatsu, Kazumasa; Itô, Shôsuke; Miura, Masami; Aosaki, Toshihiko; Itohara, Shigeyoshi; Takahashi, Ryōsuke

doi:10.1016/j.neures.2007.08.005

Cited by 40 publications

(40 citation statements)

References 46 publications

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“…It is abundantly expressed in glial and neuronal cells in several brain regions, including dopaminergic cells of the substantia nigra, and has been reported to have a role in dopaminergic signalling (Marazziti et al, 2004(Marazziti et al, , 2007Imai et al, 2007). Incidentally, GPR37 has been implicated in certain brain disorders (Imai et al, 2001;Fujita-Jimbo et al, 2012;Tomita et al, 2013), the most widely acknowledged of which is the autosomal recessive juvenile parkinsonism (AR-JP), an early onset familial Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

Mattila

Tuusa

Petäjä-Repo

2016

Journal of Cell Science

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The G-protein-coupled receptor 37 ( GPR37) has been implicated in the juvenile form of Parkinson's disease, in dopamine signalling and in the survival of dopaminergic cells in animal models. The structure and function of the receptor, however, have remained enigmatic. Here, we demonstrate that although GPR37 matures and is exported from the endoplasmic reticulum in a normal manner upon heterologous expression in HEK293 and SH-SY5Y cells, its long extracellular N-terminus is subject to metalloproteinase-mediated limited proteolysis between E167 and Q168. The proteolytic processing is a rapid and efficient process that occurs constitutively. Moreover, the GPR37 ectodomain is released from cells by shedding, a phenomenon rarely described for GPCRs. Immunofluorescence microscopy further established that although full-length receptors are present in the secretory pathway until the trans-Golgi network, GPR37 is expressed at the cell surface predominantly in the N-terminally truncated form. This notion was verified by flow cytometry and cell surface biotinylation assays. These new findings on the GPR37 N-terminal limited proteolysis may help us to understand the role of this GPCR in the pathophysiology of Parkinson's disease and in neuronal function in general.

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Section: Introductionmentioning

confidence: 99%

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

Mattila

Tuusa

Petäjä-Repo

2016

Journal of Cell Science

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“…Although parkin has many substrates (11), GPR37 may be one of the key substrates related to pathology in patients with parkin mutations, which are associated with autosomal recessive juvenile Parkinson disease (9,12,13). The connection between GPR37 and parkin has led to a focus on the dopaminergic system in GPR37 knockout mice, which exhibit a reduced dopaminergic tone and various subtle perturbations in dopaminergic signaling in the brain (14)(15)(16). However, GPR37 and GPR37L1 are expressed in many different brain regions beyond just dopaminergic areas, so it seems probable that these receptors play a broader role in the regulation of neuronal and glial physiology beyond simply modulating dopaminergic neurotransmission.…”

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confidence: 99%

GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin

Meyer

Giddens

Schaefer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

181

237

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GPR37 (also known as Pael-R) and GPR37L1 are orphan G protein-coupled receptors that are almost exclusively expressed in the nervous system. We screened these receptors for potential activation by various orphan neuropeptides, and these screens yielded a single positive hit: prosaptide, which promoted the endocytosis of GPR37 and GPR37L1, bound to both receptors and activated signaling in a GPR37- and GPR37L1-dependent manner. Prosaptide stimulation of cells transfected with GPR37 or GPR37L1 induced the phosphorylation of ERK in a pertussis toxin-sensitive manner, stimulated 35 S-GTPγS binding, and promoted the inhibition of forskolin-stimulated cAMP production. Because prosaptide is the active fragment of the secreted neuroprotective and glioprotective factor prosaposin (also known as sulfated glycoprotein-1), we purified full-length prosaposin and found that it also stimulated GPR37 and GPR37L1 signaling. Moreover, both prosaptide and prosaposin were found to protect primary astrocytes against oxidative stress, with these protective effects being attenuated by siRNA-mediated knockdown of endogenous astrocytic GPR37 or GPR37L1. These data reveal that GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin.

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“…A number of alterations in the development of PD have been reported in GPR37-/-mice; for instance, it has been shown an increased resistance to MPTP-induced neurotoxicity [20]. The absence of this orphan receptor has been therefore considered to have a neuroprotective role, although other studies have proposed the use of GPR37 ligands as neuroprotective agents [4].…”

Section: Page 6 Of 16mentioning

confidence: 99%

“…Furthermore, GPR37 has also been linked to the dopaminergic system, both in a connection between its expression to striatal dopamine levels [20], and between changes in its subcellular location to the presence of dopamine receptors [5]. Hence, a much more sophisticated scenario would be depicted, in which other receptors (e.g.…”

Section: Page 6 Of 16mentioning

confidence: 99%

Adenosine A2A receptor-mediated control of pilocarpine-induced tremulous jaw movements is Parkinson's disease-associated GPR37 receptor-dependent

Gandía

Morató

Štagljar

et al. 2015

Behavioural Brain Research

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Pael receptor is involved in dopamine metabolism in the nigrostriatal system

Cited by 40 publications

References 46 publications

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin

Adenosine A2A receptor-mediated control of pilocarpine-induced tremulous jaw movements is Parkinson's disease-associated GPR37 receptor-dependent

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