4.6 GPR158
GPR158 is a class C oGPCR, discovered in 2005 through genome assembly and GPCR gene predictions (Bjarnadottir et al., 2005). It is one of the most abundant oGPCRs in the brain, expressed throughout the CNS, including the prefrontal cortex, hippocampus, striatum and cortex (Chang et al., 2023). Interestingly, GPR158 does not signal through traditional class C GPCR mechanisms, instead it localises regulator of G protein signalling 7 (RGS7), Gβ5 and allosterically promotes GTPase activity of Gαi/o (Hajj et al., 2019). This ultimately reduces the activity of adenylate cyclase and influences downstream signalling pathways and subsequent behaviour (Hajj et al., 2019; Orlandi et al., 2015; Song et al., 2019). Previously, osteocalcin (OCN) and heparan sulphate proteoglycans (HSPGs) were proposed ligands for GPR158 (Khrimian et al., 2017). Further, a recent study suggests that glycine acts as an endogenous ligand at GPR158, inhibiting formation of the RGS7–Gβ5 complex and adenosine 3′,5′-monophosphate to regulate neuronal excitability, suggesting this GPCR may have been adopted as a metabotropic glycine receptor (Laboute et al., 2023), however, further validation is required. The crystal structure of GPR158 both alone and bound to RSG7 and Gβ5 have recently been solved by two groups (Jeong et al., 2021; Patil et al., 2022), which may accelerate drug discovery and development GPR158 ligands.
GPR158 has been implicated in depressive disorders. In humans,GPR158 mRNA is upregulated in the PFC of individuals with major depressive disorder, which is conserved in rodent models of stress-induced depressive behaviour and can be rescued through genetic manipulation of GPR158 (Sutton et al., 2018). Interestingly, our recent genome-wide RNAseq analysis showed reduced GPR158 expression within the striatum of individuals with AUD (Walker et al., 2020), suggesting region-specific actions and regulation of GPR158 may occur. Given the link between stress, depression and alcohol use (Boden & Fergusson, 2011; Gilpin et al., 2015; Sinha, 2012; Walker, 2021), GPR158 may also be effective for the treatment of alcohol and substance use disorders. GPR158 has recently been shown to mediate sensitivity to the sedative effects of ethanol (Wei et al., 2023). Thus, GPR158 null mice had a deficit in recovery from a sedative dose of alcohol (3.5 mg/kg) without altering alcohol metabolism or basal differences in locomotor activity, or basal anxiety-like behaviour (Wei et al., 2023). Further using a GPR158 floxed mouse, they showed that this effect was in part driven by GPR158 expression on both glutamatergic and GABAergic populations in the brain (Wei et al., 2023). However, studies to date have not reported the effect of either knockout mice, or selective drug targets, in reducing alcohol or drug consumption, self-administration or relapse.