Editorial

3 pages, 180 KiB

Open AccessEditorial

by Daniela Marazziti

Int. J. Mol. Sci. 2023, 24(7), 6722; https://doi.org/10.3390/ijms24076722 - 04 Apr 2023

Cited by 2 | Viewed by 1016

The vertebrate G protein-coupled receptors 37 and 37-like 1 (GPR37 and GPR37L1) were discovered more than two decades ago, and they have been implicated in various neurological and neurodegenerative diseases, as well as in inflammatory pain and tumorigenesis [...] Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

Research

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19 pages, 4377 KiB

Open AccessArticle

G Protein-Coupled Receptor 37L1 Modulates Epigenetic Changes in Human Renal Proximal Tubule Cells

by Ines Armando, Santiago Cuevas, Caini Fan, Megha Kumar, Zahra Izzi, Pedro A. Jose and Prasad R. Konkalmatt

Int. J. Mol. Sci. 2022, 23(22), 14456; https://doi.org/10.3390/ijms232214456 - 21 Nov 2022

Cited by 2 | Viewed by 1627

Abstract

Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and [...] Read more.

Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Recently, we showed that GPCR 37L1 (GPR37L1) is expressed on the apical membrane of renal proximal tubules (RPT) and regulates luminal sodium transport and blood pressure by modulating the function of the sodium proton exchanger 3 (NHE3). However, little is known about GPR37L1 intracellular signaling. Here, we show that GPR37L1 is localized to the nuclear membrane, in addition to the plasma membrane in human RPT cells. Furthermore, GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhance NHE3 transcription. Overall, we demonstrate the direct role of a nuclear membrane GPCR in the regulation of renal sodium through epigenetic gene regulation. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

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17 pages, 3380 KiB

Open AccessArticle

Impaired Aversive Memory Formation in GPR37L1KO Mice

by Vandana Veenit, Xiaoqun Zhang, Wojciech Paslawski, Ioannis Mantas and Per Svenningsson

Int. J. Mol. Sci. 2022, 23(22), 14290; https://doi.org/10.3390/ijms232214290 - 18 Nov 2022

Cited by 1 | Viewed by 1450

Abstract

GPR37L1 is an orphan G-protein-coupled receptor, which is implicated in neurological disorders, but its normal physiological role is poorly understood. Its close homologue, GPR37, is implicated in Parkinson’s disease and affective disorders. In this study, we set out to characterize adult and middle-aged [...] Read more.

GPR37L1 is an orphan G-protein-coupled receptor, which is implicated in neurological disorders, but its normal physiological role is poorly understood. Its close homologue, GPR37, is implicated in Parkinson’s disease and affective disorders. In this study, we set out to characterize adult and middle-aged global GPR37L1 knock-out (KO) mice regarding emotional behaviors. Our results showed that GPR37L1KO animals, except adult GPR37L1KO males, exhibited impaired retention of aversive memory formation as assessed by the shorter retention latency in a passive avoidance task. Interestingly, the viral-mediated deletion of GPR37L1 in conditional knockout mice in the hippocampus of middle-aged mice also showed impaired retention in passive avoidance tasks, similar to what was observed in global GPR37L1KO mice, suggesting that hippocampal GPR37L1 is involved in aversive learning processes. We also observed that middle-aged GPR37L1KO male and female mice exhibited a higher body weight than their wild-type counterparts. Adult and middle-aged GPR37L1KO female mice exhibited a reduced level of serum corticosterone and middle-aged GPR37L1KO females showed a reduced level of epinephrine in the dorsal hippocampus in the aftermath of passive avoidance task, with no such effects observed in GPR37L1KO male mice, suggesting that lack of GPR37L1 influences behavior and biochemical readouts in age- and sex-specific manners. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

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19 pages, 16069 KiB

Open AccessArticle

The Effect of Early Life Stress on Emotional Behaviors in GPR37KO Mice

by Vandana Veenit, Xiaoqun Zhang, Antonio Ambrosini, Vasco Sousa and Per Svenningsson

Int. J. Mol. Sci. 2022, 23(1), 410; https://doi.org/10.3390/ijms23010410 - 30 Dec 2021

Cited by 7 | Viewed by 2125

Abstract

GPR37 is an orphan G-protein-coupled receptor, a substrate of parkin which is linked to Parkinson’s disease (PD) and affective disorders. In this study, we sought to address the effects of early life stress (ELS) by employing the paradigm of limited nesting material on [...] Read more.

GPR37 is an orphan G-protein-coupled receptor, a substrate of parkin which is linked to Parkinson’s disease (PD) and affective disorders. In this study, we sought to address the effects of early life stress (ELS) by employing the paradigm of limited nesting material on emotional behaviors in adult GPR37 knockout (KO) mice. Our results showed that, while there was an adverse effect of ELS on various domains of emotional behaviors in wild type (WT) mice in a sex specific manner (anxiety in females, depression and context-dependent fear memory in males), GPR37KO mice subjected to ELS exhibited less deteriorated emotional behaviors. GPR37KO female mice under ELS conditions displayed reduced anxiety compared to WT mice. This was paralleled by lower plasma corticosterone in GPR37KO females and a lower increase in P-T286-CaMKII by ELS in the amygdala. GPR37KO male mice, under ELS conditions, showed better retention of hippocampal-dependent emotional processing in the passive avoidance behavioral task. GPR37KO male mice showed increased immobility in the forced swim task and increased P-T286-CaMKII in the ventral hippocampus under baseline conditions. Taken together, our data showed overall long-term effects of ELS—deleterious or beneficial depending on the genotype, sex of the mice and the emotional context. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

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Review

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13 pages, 3012 KiB

Open AccessReview

Inflammation and Infection in Pain and the Role of GPR37

by Qin Zhang, Sangsu Bang, Sharat Chandra and Ru-Rong Ji

Int. J. Mol. Sci. 2022, 23(22), 14426; https://doi.org/10.3390/ijms232214426 - 20 Nov 2022

Cited by 10 | Viewed by 3026

Abstract

Inflammation is known to cause pain, and pain is of one of the cardinal signs of inflammation. Mounting evidence suggests that acute inflammation also resolves pain through specialized pro-resolving mediators (SPMs) and macrophage signaling. GPR37 is expressed by neurons and oligodendrocytes in the [...] Read more.

Inflammation is known to cause pain, and pain is of one of the cardinal signs of inflammation. Mounting evidence suggests that acute inflammation also resolves pain through specialized pro-resolving mediators (SPMs) and macrophage signaling. GPR37 is expressed by neurons and oligodendrocytes in the brain and has been implicated in multiple disorders, such as demyelination, Parkinson’s disease, stroke, and cancer. Recent studies have demonstrated that GPR37 is expressed by macrophages and confers protection against infection by bacteria and parasites. Furthermore, GPR37 promotes the resolution of inflammatory pain and infection-induced pain, as the duration of pain after tissue injury and infection is prolonged in mice lacking Gpr37. Mechanistically, activation of GPR37 enhances macrophage phagocytosis, and Gpr37-deficient macrophages exhibit dysregulations of pro-inflammatory and anti-inflammatory cytokines, switching from M2- to M1-like phenotypes. We also discuss novel ligands of GPR37, including neuroprotectin D1 (NPD1), a SPM derived from docosahexaenoic acid (DHA), and bone-derived hormone osteocalcin (OCN), which can suppress oligodendrocyte differentiation and myelination. NPD1 stimulates macrophage phagocytosis via GPR37 and exhibits potent analgesic actions in various animal models of inflammatory and neuropathic pain. Targeting GPR37 may lead to novel therapeutics for treating inflammation, infection, pain, and neurological diseases. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

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13 pages, 1788 KiB

Open AccessReview

GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts

by Adrià Pla-Casillanis, Laura Ferigle, Marta Alonso-Gardón, Efren Xicoy-Espaulella, Ekaitz Errasti-Murugarren, Daniela Marazziti and Raúl Estévez

Int. J. Mol. Sci. 2022, 23(10), 5528; https://doi.org/10.3390/ijms23105528 - 16 May 2022

Cited by 3 | Viewed by 2247

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects in MLC1 or glial cell adhesion molecule (GlialCAM) proteins. In addition, autoantibodies to GlialCAM are involved in the pathology of multiple [...] Read more.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects in MLC1 or glial cell adhesion molecule (GlialCAM) proteins. In addition, autoantibodies to GlialCAM are involved in the pathology of multiple sclerosis. MLC1 and GLIALCAM genes encode for membrane proteins of unknown function, which has been linked to the regulation of different ion channels and transporters, such as the chloride channel VRAC (volume regulated anion channel), ClC-2 (chloride channel 2), and connexin 43 or the Na⁺/K⁺-ATPase pump. However, the mechanisms by which MLC proteins regulate these ion channels and transporters, as well as the exact function of MLC proteins remain obscure. It has been suggested that MLC proteins might regulate signalling pathways, but the mechanisms involved are, at present, unknown. With the aim of answering these questions, we have recently described the brain GlialCAM interactome. Within the identified proteins, we could validate the interaction with several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptors GPR37L1 and GPR37. In this review, we summarize new aspects of the pathophysiology of MLC disease and key aspects of the interaction between GPR37 receptors and MLC proteins. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

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13 pages, 323 KiB

Open AccessReview

Mouse Mutants of Gpr37 and Gpr37l1 Receptor Genes: Disease Modeling Applications

by Marzia Massimi, Chiara Di Pietro, Gina La Sala and Rafaele Matteoni

Int. J. Mol. Sci. 2022, 23(8), 4288; https://doi.org/10.3390/ijms23084288 - 13 Apr 2022

Cited by 3 | Viewed by 2431

Abstract

The vertebrate G protein–coupled receptor 37 and G protein–coupled receptor 37-like 1 (GPR37 and GPR37L1) proteins have amino acid sequence homology to endothelin and bombesin-specific receptors. The prosaposin glycoprotein, its derived peptides, and analogues have been reported to interact with and activate both [...] Read more.

The vertebrate G protein–coupled receptor 37 and G protein–coupled receptor 37-like 1 (GPR37 and GPR37L1) proteins have amino acid sequence homology to endothelin and bombesin-specific receptors. The prosaposin glycoprotein, its derived peptides, and analogues have been reported to interact with and activate both putative receptors. The GPR37 and GPR37L1 genes are highly expressed in human and rodent brains. GPR37 transcripts are most abundant in oligodendrocytes and in the neurons of the substantia nigra and hippocampus, while the GPR37L1 gene is markedly expressed in cerebellar Bergmann glia astrocytes. The human GPR37 protein is a substrate of parkin, and its insoluble form accumulates in brain samples from patients of inherited juvenile Parkinson’s disease. Several Gpr37 and Gpr37l1 mouse mutant strains have been produced and applied to extensive in vivo and ex vivo analyses of respective receptor functions and involvement in brain and other organ pathologies. The genotypic and phenotypic characteristics of the different mouse strains so far published are reported and discussed, and their current and proposed applications to human disease modeling are highlighted. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

14 pages, 1154 KiB

Open AccessReview

Emerging Roles for the Orphan GPCRs, GPR37 and GPR37 L1, in Stroke Pathophysiology

by Sabra Mouhi, Breona Martin and Sharon Owino

Int. J. Mol. Sci. 2022, 23(7), 4028; https://doi.org/10.3390/ijms23074028 - 05 Apr 2022

Cited by 4 | Viewed by 3325

Abstract

Recent studies have shed light on the diverse and complex roles of G-protein coupled receptors (GPCRs) in the pathophysiology of stroke. These receptors constitute a large family of seven transmembrane-spanning proteins that play an intricate role in cellular communication mechanisms which drive both [...] Read more.

Recent studies have shed light on the diverse and complex roles of G-protein coupled receptors (GPCRs) in the pathophysiology of stroke. These receptors constitute a large family of seven transmembrane-spanning proteins that play an intricate role in cellular communication mechanisms which drive both tissue injury and repair following ischemic stroke. Orphan GPCRs represent a unique sub-class of GPCRs for which no natural ligands have been found. Interestingly, the majority of these receptors are expressed within the central nervous system where they represent a largely untapped resource for the treatment of neurological diseases. The focus of this review will thus be on the emerging roles of two brain-expressed orphan GPCRs, GPR37 and GPR37 L1, in regulating various cellular and molecular processes underlying ischemic stroke. Full article

(This article belongs to the Special Issue GPR37 and Related Receptors: Disease Regulation)

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