Bjarnadottir, et al. assembled G Protein Coupled Receptor 158 (GPR158) R158 in 2005 and clustered vertebrate glutamate G-protein-coupled receptors (GPCRs) into four phylogenetic groups (Group I: V2R, TAS1R, GPRC6A and CASR; Group II: GRM; Group III: GABA, GPR158 and GPR158L; Group IV: GPRC5) ^[1][20]. Furthermore, they clarified that GPCR 158 (or GPR158) notably appeared in mammals, but not in fish, although there is evidence to show its expression in killifish ^[2][21]. The GPR158 gene is only present in vertebrates and highly conserved in chimpanzees, monkeys, dogs, cows, mice, rats, chickens, zebrafish and frogs. Although GPR158 was assembled in D. melanogaster, it did not obtain hits upon reverse position through a specific BLAST (RPS-BLAST) search ^[1][20]. GPR158 has a paralogue named GPR179. GPR179-encoded protein has an EGF-like calcium-binding domain and a seven-transmembrane domain (7TM) in the N-terminal region. Mutations in the Gpr179 gene are associated with congenital stationary night blindness ^[3][22]. In the NCBI gene annotation, the EGF-like calcium-binding domain was only in lower vertebrates, though the physiological function of the domain awaits further investigation ^[4][23]. The evolutionary history of GPR158 and GPR179 is a subject that needs to be studied further.

In later functional research, the Martemyanov group first identified that GPR158 controlled the localization and activity of regulator of G protein signaling (RGS) 7 and Gβ protein ^[5][24]. RGS7, as well as RGS6, RGS9 and RGS11, belongs to members of the R7 subfamily of RGS proteins that are highly expressed in neurons and play a role in multiple physiological processes ^[6][25]. GPR158 binding with RGS7 could negatively modulate Gi/o signaling ^[7][26]. G proteins are usually composed of α, β and γ subunits, and are divided into four families according to their Gα subunit composition: Gs/olf, Gi/o, Gq/11 and G12/13 ^[8][27]. In response to extracellular stimuli, GPCRs transduce signals downwards through G proteins, while each G protein activates distinct signaling pathways that enable divergent physiological processes ^[8][27]. The Fini laboratory reported that glucocorticoid (GC) treatment increases GPR158 mRNA and protein, and stimulates cell proliferation ^[9][28]. Recently, several research groups found that GPR158 could interact with several members of the heterogeneous family of cell-surface and secreted heparan sulfate proteoglycans (HSPGs) and osteocalcin (OCN) ^[10][11][12][29,30,31]. However, the functions of GPR158 are still largely unknown, although studies indicate an emerging key role in the nervous system and in cancer.

Class C GPCRs have a sizeable N-terminal domain, and almost all carry a bi-lobal VFD, homologous to the periplasmic bacterial proteins that bind amino acids and ions, and a cysteine-rich domain between the VFD and 7TM (also known as heptahelical domain). The orthosteric ligands of the receptors bind between the lobes of the VFD domains, inducing the closed conformation of the VFD. When the 7TM domain of class C GPCR without the extracellular N-terminus is expressed, it could still be activated by positive allosteric modulators binding within it as class A GPCRs are activated by their orthosteric agonists ^[13][14][32,33]. Some class C receptors are homodimers (e.g., calcium-sensing receptor and metabotropic glutamate receptors (mGluRs)), whereas others are heterodimers consisting of two different protomers (GABAB receptors ^[15][34], sweet and umami taste receptors; mGluRs can also form heterodimers within subfamilies ^[16][17][35,36]). Interestingly, only one VFD from one protomer of the GABAB receptor binds the ligand, whilst the 7TM of the other protomer couples to a G protein ^[15][34], suggesting that the allosteric interactions between VFD and 7TM domains are necessary for receptor activation ^[18][5]. Inter-domain allosteric interactions and functional asymmetry, where only one protomer couples the G protein, appear common to all class C receptors. In homodimeric mGluRs, the agonist binding one VFD can activate this receptor, while binding both VFDs can further enhance the activity ^[18][5].

Since GPR158 was discovered, its functional research in the nervous system has been inseparable from RGS7. Patil, et al. reported the structures of the human GPR158 alone and bound with RGS7-Gβ5 employing single-particle cryogenic electron microscopy (cryoEM) recently ^[19][44]. Jeong, E., et al. also reported the cryo-EM structures of GPR158 alone and with RGS7-Gβ5 ^[20][45]. The structures of GPR158 stabilized by a pair of phospholipids and the complex of one RGS7–Gβ5 heterodimer were at an average resolution of 3.4 Å and 3.3 Å, respectively ^[19][44]. The overall architecture of GPR158 is composed of three parts: (1) a large N-terminus containing a signal peptide (AA 1-23) and multiple potential N-glycosylation sites (AA 98, 143, 215 and 274), (2) a canonical 7TM with three extracellular loops (ECL1-3) at the extracellular side intermingled with three intracellular loops (ICL1-3) at the intracellular side, and (3) an extended C-terminal region ^[21][46].

The N-terminal portion of the extracellular domain (ECD) of GPR158 adopts a previously unrecognized characteristic Cache (calcium channels and chemotaxis receptors) domain in GPCRs ^[19][44], in which the Leucine zipper domains could recognize a specific DNA sequence and mediate dimerization ^[22][47]. The EGF-like calcium-binding domain may be crucial for numerous protein–protein interactions. The cysteine-rich domain (CRD) plays a role in receptor activation ^[23][41]. ECL2 C573 forms a conservative disulfide bond with TM3 C481, which is a conserved interaction conserved throughout many other GPCRs, and the disulfide bonds are essential for ligand recognition ^[19][24][25][44,48,49].

In the intracellular domain of GPR158, the KXXR motif in TM3 and the residue E (AA 609) in ICL3 are presumed to be involved in the activation of Family C GPCRs ^[9][28]. The bipartite nuclear-localization-signal (NLS) motif located in the C-terminus of GPR158, LKKLY and KRKK is essential for the nuclear entry ^[9][28]. Specific sequences for binding of transcription factors, such as c-Myc and Pitx2, are also found in the C-terminus of GPR158 ^[9][28]. As is known, MYC controls cell proliferation, while PITX2 is involved in the regulation of cell differentiation and organ development ^{[26][27][28][29]}[50,51,52,53]. Upon translocation to the nucleus, it is likely that GPR158 interacts with these transcription factors. The two conserved VCPWE motifs in the GPR158 C-terminal tail regulate the interactions between GPR158 and G_o ^[7][26]. It is worth noting that GPR158 exhibits constitutive activity for Gi/o proteins, but not for Gq ^[30][54]. Interestingly, GPR158 localizes RGS7–Gβ5 and the activated Gαi/o protein ^[7][31][26,55]. Three serines in the C-terminal extracellular domain of GPR158 are the putative phosphorylation sites for protein kinases involving cell proliferation, such as CDK1 ^[9][32][28,56]. Taken together, the structural information for GPR158 provides insights into the unusual biology of the orphan receptors and the noncanonical signaling mechanism by which GRP158 selectively recruits the RGS7–Gβ5 complex.

GPR158 is highly expressed in the brain and its expression shown to be specific in nervous system-related tumors ^[33][17]. Recent studies have shown that GPR158 may quantitatively characterize the malignant process of glioma (i.e., GPR158 expression was highest in the central nervous system (CNS) and oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma and IDH wild-type glioblastoma) ^[33][17]. Remarkably, GPR158 may switch the glioma phenotypic plasticity via the downregulation of proliferation, migration and glioma stem-like cell formation, and via the induction of proneural differentiation and apoptosis simultaneously ^[33][17]. The neural differentiation of stem and progenitor cells is associated with apoptotic cell death ^[34][57]. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggest a possible role for GPR158 as a prognostic biomarker and a therapeutic target in human gliomas. It is worth noting that there was also some transcriptomic evidence of a common pathogenesis pathway in MDD (Major Depressive Disorder) and GBM ^[35][58]. In keeping with these findings, GPR158 becomes hypermethylated with the decreased expression of the invasive melanoma cells, which may affect the neural crest differentiation pathway and the regulation of the actin cytoskeleton ^[36][59]. GPR158 is also hypermethylated in many esophageal squamous cell carcinoma (ESCC) samples and can be used as a risk factor marker ^[37][60].

Further reports in the literature may highlight a causative role of GPR158 in human health and disease ^[44][66]. SomWe follows:

(1)Deregulatling cellular metabolism: An mRNA microarray study on the subnuclear structures of the mouse brain suggested that habenular GPR158 might be involved in food consumption and energy expenditure (EE) ^[45]. Singt some as fole nucleotide polymorphisms (SNPs) of GPR158 were found to be associated with a lower energy expenditure (EE) and adiposity in Native Americans ^[46]. As a known intracellular interacting protein of GPR158, RGS7 is at an obesity locus in humans ^[47] and as a putative agonist of GPR158, OCN mediates insulin signals in glucose metabolism ^[48], which indicated that GPR158 might influence tumor development and neuropsychiatric diseases through energy metabolism.

(2)Avoiding immune destructionows: SNPs of the GPR158 gene were shown to be potentially liked to humoral immunity to smallpox vaccination ^[49] and to hepatitis C virus (HCV) clearance in patients of European and African ancestry ^[50]. These findings expand the relationship existing between GPR158 and neuronal activity towards its possible role in neuro-immune cross-talk.

Studies have been carried out to uncover the molecular mechanisms of GPR158 in the vast complexity of cancer phenotypes and genotypes. Fini investigated glucocorticoid (GC)-induced ocular hypertension (OH) ^[9][28]. Genecard expression data suggested that the mRNA is widely expressed in normal human tissues, while the protein is expressed only in the retina and prefrontal cortex. In keeping, the GPR158 protein expression was not detected until treated with the glucocorticoids dexamethasone (Dex) for six days or triamcinolone acetonide (TA) for eight days in cultured trabecular meshwork (TBM) cells ^[9][28]. GPR158 overexpression was linked to ocular hypertension, associated with TP53 pathway activation and enhanced cyclic adenosine 3′,5′-monophosphate (cAMP) production in response to epinephrine ^[54][76]. Of note, significantly higher levels of cAMP were nonetheless found in the medial prefrontal cortex (mPFC) of the Gpr158^−/− mice ^[55][18]. Taken together, GPR158 may develop into a uniquely effective drug target for ocular hypertension and glaucoma ^[21][46] in the future. It was also found that GPR158 can interact with androgen receptors to modulate tumor cell proliferation via lowering the responding threshold to androgen during androgen deprivation therapy ^[38][16]. To date, GPR158 presents an intriguing target for prevention and therapy of castration-resistant prostate cancer (CRPC) ^[56][77].

It isWe identified a target-dependent effect of microRNA-449a in inhibiting cell growth and migration by the downregulation of CCND1 and in suppressing neural phenotypes by the downregulation of GPR158 ^[33][17]. GPR158 can regulate the malignant phenotype of glioma, and, as a biomarker, quantitatively characterize the malignant process of glioma independent from the miR-449a target CCND1 (the expression of CCND1 remains largely independent of the tumor subtype ^[33][17]). Strikingly, GPR158 with a mutated NLS was internalized in small endocytic vesicles and retained in the cytoplasm, while the treatment of an inhibitor of endocytosis resulted in GPR158 trafficking to the plasma membrane. Failing to fulfil its functions in the nucleus, membrane GPR158 was not able to enhance cell proliferation ^[9][28]. The subcellular location of GPR158 may explain why it plays a different role in nervous system and somatic tumors.

GPR158 is extensively expressed in CNS, particularly in the prefrontal cortex (PFC), striatum and hippocampus, where it controls synapse formation and function ^{[5][10][55][57]}[18,24,29,78]. GPR158 has been demonstrated to be implicated in the etiology of affective disorders, for instance, memory loss, cognitive diseases and depression ^{[52][55][58][59]}[18,19,39,74], mainly attributed to the fact that GPR158 plays a critical role in the structural organization and functional formation of the synapse. It was confirmed that a germline knockout (KO) of GPR158 could result in the interrupted dendritic structures of CA1 and CA3 circuits in the mouse hippocampus ^[10][57][29,78]. GPR158 deletion undermines the bouton morphology and ultrastructural organization of the active zone, decreases the density of postsynaptic terminals, augments the density of mossy fiber synapses and reduces synaptic transmission without affecting the adjacent inputs on the same dendrite ^[5][10][24,29].

GPR158 plays a part in mediating chronic stress-induced depression. A global abolishment of GPR158 led to an anti-depressive phenotype in mice, characterized by a lower susceptibility to learned helplessness and reduced anhedonia ^[55][58][18,19]. The rats exposed to chronic unpredictable stress (CUS) showed higher serum glucocorticoid (GC) level and anxiety-like behavior, but not depressive-like behavior, in the absence of GC production ^[60][79]. The persistent exposure to chronic stress could also enhance the expression level of GPR158 in mPFC in a GC-dependent fashion. GC increased the expression of GPR158 at the transcriptional and translational level ^[9][60][61][28,79,80], which suggests a role of the glucocorticoids–GPR158 axis in anxiety and depression. During the transition from a stressful state to depression, increased GPR158 expression induced by long-lasting stress resulted in RGS7 being directed to the plasma membrane, and this GPR158–RGS7 complex modulated the function of the GTPase accelerating protein (GAP) complex to regulate adenylate cyclase (AC) and cAMP production in the mPFC ^[5][58][19,24]. Further, Itakura, et al. found that GPR158 maintained the homeostasis of intraocular pressure, while GPR158 deficiency caused the inhibition of ageing-induced stress in the visual system ^[54][76]. These findings suggest new avenues for pharmacological interventions in affective disorders.

Of interest, postsynaptic GPR158 can bind cell surface glypican 4 (GPC4) to form synapse-organizing protein complexes, which can induce presynaptic differentiation and selectively mediate the formation of synaptic architecture and the function of mossy fiber-CA3 synapses ^[10][29]. GPR158 could mediate OCN’s regulation of hippocampal-dependent memory ^[12][31]. Furthermore, GPR158 ameliorates age-dependent memory loss mediated by the histone-binding protein RbAp48 through OCN/GPR158 signaling ^[52][74]. It is interesting that embryonic osteocalcin could regulate postnatal adrenal steroid through the GPR158 receptor ^[62][81]. This finding postulated translational potential as to whether modulating osteocalcin levels could promote endogenous adrenocortical function in adrenocortical hypoplasia and glucocorticoid deficiency ^[61][80]. Of importance, GPR158 appears to be correlated with ageing and cardiac diseases caused by aFGF (acidic fibroblast growth factor)-induced collagen deposition ^[51][73] and associated with the atrophy pattern ^[63][82] and Alzheimer’s Disease ^[64][83], which may be indicative for GPR158 in age-onset diseases ^[65][84]. There are data showing that GPR158 signaling could affect the brain-derived neurotrophic factor (BDNF) via the protein RbAp48 in the hippocampus and mPFC ^[52][74]. Fibroblast growth factor (FGF) may also influence GPR158 expression and could play a role in the differentiation of cardiac fibroblasts ^[51][66][73,85].