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.