Orphan GPR52 as an emerging neurotherapeutic target

Abstract

GPR52 is a highly conserved, brain-enriched, G_s/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL'149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.

Keywords: GPR52; Huntington’s disease; agonists; central nervous system disorders; drug discovery; orphan GPCR; schizophrenia.

FIGURE 1

GPR52 mRNA transcript expression in human tissues and brain, generated from the GTEx RNAseq results and online database (GTEx data at: https://www.gtexportal.org/home/gene/GPR52). (a) The total percentage of GPR52 mRNA expression in human tissues shows highly enriched expression in the brain. (b) GPR52 median transcripts per million mRNA expression in human brain subregions determined by GTEx.

FIGURE 2

Sequence and structures of GPR52. (a) The sequence of GPR52, colored to represent different domains: TM1 (cyan), TM2 (yellow), TM3 (blue), TM4 (orange), TM5 (light blue), TM6 (magenta), TM7 (green), ECL2 (red), ICL3 (gray) and H8 (light green). (b) The crystal structures of GPR52 [displayed in the same colors as its sequences in (a)] and its ICL3 fusion-protein partner (rubredoxin, brown) (PDB code: 6LI2). (c) The crystal structures of GPR52 [displayed in the same colors as in (a)] and its ICL3 fusion-protein partner (flavodoxin, brown) (PDB code: 6LI1). (d) The co-crystal structure of the GPR52–mini-G_s–Nb35 complex (GPR52, red; mini-G_αs, blue; G_β, green; G_γ, purple; Nb35 nanobody, yellow) (PDB code: 6LI3). (e) The co-crystal structure of GPR52 [displayed in the same colors as in (a)] and an agonist c17 (compound 5, purple sphere) in the complex (PDB code: 6LI0).

FIGURE 3

A brief schematic of GPR52 signaling pathways in MSNs and potential interactions with DAR signaling, such as with D₂R/D₃R. GPR52 couples to G_s or G_olf (Gs/olf proteins consist of G_αs or G_αolf, G_β, and G_γ) and promotes AC conversion of ATP to cAMP. cAMP regulates various cellular responses through PKA directly, or PKA can result in further phosphorylation of CREB to regulate gene expression and mediate cellular responses. Activated GPR52 promotes the accumulation of cAMP, thereby increasing the activity of an unknown GEF protein and activating Rab39B protein-mediated cellular functions such as HTT expression. In addition, GPR52 can recruit and couple to β-arrestins to activate ERK signaling. D₂R and D₃R couple to G_i (G_i protein consists of G_αi, G_β and G_γ) to inhibit the activity of AC and reduce cAMP signaling. The convergence of the signaling between GPR52 and the D₂R has supported the general concept that GPR52 agonists could resemble D₂R antagonists.

FIGURE 4

Small-molecule GPR52 ligands and co-crystal structures (PDB code: 6LI0) of compound 5 in complex with GPR52. (a) Chemical structures of reported representative small-molecule GPR52 regulators. (b) The binding pocket of the co-crystal structure with compound 5 (purple) and GPR52. Important residues are drawn as sticks, and hydrogen bonds are shown as dashed yellow lines. (c) The co-crystal structure of compound 5 and GPR52 in 2D binding pocket view. Hydrogen bonds are shown as purple lines and the p-p interaction is shown as a green line.