Glio‐ and neuro‐protection by prosaposin is mediated by orphan G‐protein coupled receptors GPR37L1 and GPR37

Liu, Beihui; Mosienko, Valentina; Cardoso, Barbara Vaccari; Prokudina, Daria; Huentelman, Mathew; Teschemacher, Anja G.; Kasparov, Sergey

doi:10.1002/glia.23480

Cited by 66 publications

(79 citation statements)

References 46 publications

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“…The potency of LL via its action on LLRx (EC 50~0 .5 mM) should be low compared to that of other endogenous GPCR ligands. For example, NA acting at β-adrenoceptors is around three orders of magnitude more potent (see Supplement in [44]. It is, however, fully consistent with a specific response based on low-affinity binding, given the high physiological extracellular LL concentration in the brain.…”

Section: Discussionmentioning

confidence: 85%

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

et al. 2018

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The importance of astrocytic l-lactate (LL) for normal functioning of neural circuits such as those regulating learning/memory, sleep/wake state, autonomic homeostasis, or emotional behaviour is being increasingly recognised. l-Lactate can act on neurones as a metabolic or redox substrate, but transmembrane receptor targets are also emerging. A comparative review of the hydroxy-carboxylic acid receptor (HCA1, formerly known as GPR81), Olfactory Receptor Family 51 Subfamily E Member 2 (OR51E2), and orphan receptor GPR4 highlights differences in their LL sensitivity, pharmacology, intracellular coupling, and localisation in the brain. In addition, a putative Gs-coupled receptor on noradrenergic neurones, LLRx, which we previously postulated, remains to be identified. Next-generation sequencing revealed several orphan receptors expressed in locus coeruleus neurones. Screening of a selection of these suggests additional LL-sensitive receptors: GPR180 which inhibits and GPR137 which activates intracellular cyclic AMP signalling in response to LL in a heterologous expression system. To further characterise binding of LL at LLRx, we carried out a structure–activity relationship study which demonstrates that carboxyl and 2-hydroxyl moieties of LL are essential for triggering d-lactate-sensitive noradrenaline release in locus coeruleus, and that the size of the LL binding pocket is limited towards the methyl group position. The evidence accumulating to date suggests that LL acts via multiple receptor targets to modulate distinct brain functions.

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Section: Discussionmentioning

confidence: 85%

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

et al. 2018

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“…However, disentangling the specificity of TX14A/prosaposin for GPR37L1, GPR37 or neither, is problematic as many studies evaluating the potential agonist activity of this ligand have used models in which both receptors are inactivated. For example, Liu et al (51) showed that simultaneous knockdown of both GPR37 and GPR37L1 in astrocytes abolished TX14A-mediated cAMP inhibition and protection from oxidative toxicity (although intriguingly, they could not replicate TX14A activation of GPR37 or GPR37L1 in HEK293 cells, the same model used in the original discovery of the pairing (16).…”

Section: Discussionmentioning

confidence: 99%

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

Coleman

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Smythe

et al. 2020

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GPR37L1 is an orphan G protein-coupled receptor expressed exclusively in the brain and linked to seizures, neuroprotection and cardiovascular disease. Based upon the observation that fragments of the GPR37L1 N-terminus are found in human cerebrospinal fluid, we hypothesized that GPR37L1 was subject to post-translational modification. Heterologous expression of GPR37L1-eYFP in either HEK293 or U87 glioblastoma cells yielded two cell surface species of approximately equivalent abundance, the larger of which is N-glycosylated at Asn 105 . The smaller species is produced by matrix metalloprotease/ADAMmediated proteolysis (shown by the use of pharmacological inhibitors) and has a molecular weight identical to that of a mutant lacking the entire N-terminus, Δ122 GPR37L1. Serial truncation of the Nterminus prevented GPR37L1 expression except when the entire N-terminus was removed, narrowing the predicted site of N-terminal proteolysis to residues 105-122. Using yeast expressing different G protein chimeras, we found that wild type GPR37L1, but not Δ122 GPR37L1, coupled constitutively to Gpa1/Gαs and Gpa1/Gα16 chimeras, in contrast to previous studies. We tested the peptides identified in cerebrospinal fluid as well as their putative newly-generated N-terminal 'tethered' counterparts in both wild type and Δ122 GPR37L1 Gpa1/Gαs strains but saw no effect, suggesting that GPR37L1 does not signal in a manner akin to the protease-activated receptor family. We also saw no evidence of receptor activation or regulation by the reported GPR37L1 ligand, prosaptide/TX14A. Finally, the proteolytically processed species predominated both in vivo and ex vivo in organotypic cerebellar slice preparations, suggesting that GPR37L1 is rapidly processed to a signaling-inactive form. Our data indicate that the function of GPR37L1 in vivo is tightly regulated by metalloprotease-dependent N-terminal cleavage.

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“…Several potential ligands for GPR37 have been reported, including prosaposin and its active fragment prosaptide (17)(18)(19), an invertebrate peptide called head activator that is structurally similar to prosaptide (20,21), and the bioactive lipid neuroprotectin-1 (22). There is not yet a broad consensus as to whether any or all of these ligands represent authentic endogenous ligands for GPR37, and further studies in vivo will be necessary to address this important question.…”

Section: Discussionmentioning

confidence: 99%

“…Several ligands have been reported for GPR37, although a consensus has not yet been achieved as to whether any or all of these ligands are authentic endogenous agonists. The reported ligands for GPR37 include prosaposin and its active fragment prosaptide (17)(18)(19), an invertebrate peptide related to prosaptide known as head activator peptide (20,21), and the lipid metabolite neuroprotectin D1 (22). Intriguingly, both prosaptide (23)(24)(25) and neuroprotectin D1 (26)(27)(28) have been reported to exert protective actions in rodent models of nerve injury or stroke.…”

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confidence: 99%

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

et al. 2019

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GPCR 37 (GPR37) is a GPCR expressed in the CNS; its physiological and pathophysiological functions are largely unknown. We tested the role of GPR37 in the ischemic brain of GPR37 knockout (KO) mice, exploring the idea that GPR37 might be protective against ischemic damage. In an ischemic stroke model, GPR37 KO mice exhibited increased infarction and cell death compared with wild‐type (WT) mice, measured by 2,3,5‐triphenyl‐2H‐tetrazolium chloride and TUNEL staining 24 h after stroke. Moreover, more severe functional deficits were detected in GPR37 KO mice in the adhesive‐removal and corner tests. In the peri‐infarct region of GPR37 KO mice, there was significantly more apoptotic and autophagic cell death accompanied by caspase‐3 activation and attenuated mechanistic target of rapamycin signaling. GPR37 deletion attenuated astrocyte activation and astrogliosis compared with WT stroke controls 24–72 h after stroke. Immunohistochemical staining showed more ionized calcium‐binding adapter molecule 1–positive cells in the ischemic cortex of GPR37 KO mice, and RT‐PCR identified an enrichment of Ml‐type microglia or macrophage markers in the GPR37 KO ischemic cortex. Western blotting demonstrated higher levels of inflammatory factors IL‐1β, IL‐6, monocyte chemoattractant protein, and macrophage inflammatory protein‐1α in GPR37‐KO mice after ischemia. Thus, GPR37 plays a multifaceted role after stroke, suggesting a novel target for stroke therapy.—McCrary, M. R., Jiang, M. Q., Giddens, M. M., Zhang, J. Y., Owino, S., Wei, Z. Z., Zhong, W., Gu, X., Xin, H., Hall, R. A., Wei, L., Yu, S. P. Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice. FASEB J. 33, 10680–10691 (2019). http://www.fasebj.org

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Glio‐ and neuro‐protection by prosaposin is mediated by orphan G‐protein coupled receptors GPR37L1 and GPR37

Cited by 66 publications

References 46 publications

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

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