GPR180

GPR180 is a multi-pass membrane protein that acts as a regulator of TGFβ signalling and lipid metabolism rather than as a canonical G protein-coupled receptor (PMID:34880217, PMID:39609618). Structurally it belongs to the GOST family, with a crystallographically resolved N-terminal GOLD-like domain and a seven-transmembrane region; it localises to intracellular vesicular structures and undergoes pH-dependent conformational changes that map to a putative ligand-binding site in the transmembrane region, consistent with sensing the acidic vesicular environment (PMID:39609618). Functionally, GPR180 operates downstream of CTHRC1 and upstream of the TGFβ receptor complex, promoting SMAD3 phosphorylation, and this CTHRC1/GPR180 axis is required for control of brown/beige adipocyte activity and glucose homeostasis (PMID:34880217). In the liver, GPR180 acts upstream of mTORC1/SREBP1: its loss reduces mTOR phosphorylation and SREBP1 activation and ameliorates hepatic and plasma lipids after high-fat diet, with hepatic re-expression restoring the lipid phenotype (PMID:36726016). In white adipocytes, GPR180 directly inhibits lipogenesis and fatty acid uptake, and its overexpression protects mice from diet-induced obesity while adipocyte-specific deletion worsens lipid handling (PMID:39925142).

1. 2003 Low

   Before any functional study, the genomic identity of human ITR/GPR180 had to be established, defining the locus as a candidate seven-transmembrane receptor gene associated with vascular remodeling.

   Evidence Genomic sequencing, structure determination, and SNP mapping across the 13q31 locus in 48 individuals

   PMID:12730718

   Open questions at the time

   • No functional experiment was performed on the protein itself
   • The annotation as a rhodopsin-like GPCR was inferred from sequence, not activity
   • No link to any signalling pathway or ligand was established
2. 2021 Medium

   The key question of what pathway GPR180 belongs to was answered by placing it not as a classical GPCR but as a component of TGFβ signalling acting in a CTHRC1-dependent branch.

   Evidence Knockout/knockdown and pharmacological tools in adipocyte models and mice; SMAD3 phosphorylation assays and epistasis positioning GPR180 downstream of CTHRC1 and upstream of the TGFβ receptor

   PMID:34880217

   Open questions at the time

   • No in vitro reconstitution of the GPR180–TGFβ receptor interaction
   • Direct physical binding to CTHRC1 or the receptor complex not demonstrated
   • Mechanism by which GPR180 modulates SMAD3 phosphorylation unresolved
3. 2023 Medium

   Whether GPR180 has metabolic functions beyond adipocyte thermogenesis was addressed by showing it regulates hepatic lipid metabolism upstream of mTORC1/SREBP1.

   Evidence Gpr180 knockout mice on high-fat diet, AAV8 hepatic rescue, transcriptomics, and Western blots for p-mTOR and activated SREBP1 in mouse liver and Huh7 cells

   PMID:36726016

   Open questions at the time

   • Molecular link between GPR180 and mTOR activation not defined
   • Whether the hepatic effect depends on the CTHRC1/TGFβ axis is unknown
   • No identified upstream ligand driving hepatic signalling
4. 2025 Medium

   The cell-autonomous metabolic role in white adipocytes was clarified by demonstrating GPR180 directly suppresses lipogenesis and fatty acid uptake to limit adiposity.

   Evidence AAV overexpression in subcutaneous adipose tissue, adipocyte-specific knockout mice, and lipogenesis/fatty acid uptake assays in SVF-derived adipocytes

   PMID:39925142

   Open questions at the time

   • Direct molecular effectors of lipogenesis/uptake suppression not identified
   • Relationship to the hepatic mTORC1/SREBP1 mechanism unclear
   • Whether SMAD3 signalling mediates the adipocyte phenotype not tested
5. 2024 High

   The structural and subcellular basis of GPR180 function was established by assigning it to the GOST family with a GOLD-like N-terminal domain and showing it acts within intracellular acidic vesicles.

   Evidence X-ray crystallography of the N-terminal domain (1.9 Å), cellular imaging of vesicular localization, and HDX-MS mapping of pH-dependent conformational changes

   PMID:39609618

   Open questions at the time

   • No endogenous ligand identified for the putative transmembrane binding site
   • How vesicular localization reconciles with plasma-membrane TGFβ receptor signalling is unresolved
   • Full-length structure including the transmembrane region not determined

• It remains unknown how GPR180's structural and vesicular biology mechanistically connects its disparate roles in TGFβ/SMAD3 signalling, hepatic mTORC1/SREBP1 regulation, and adipocyte lipid handling.
• No identified physiological ligand engaging the transmembrane pocket
• Direct physical partners in the TGFβ receptor complex unconfirmed
• Causal chain linking vesicular conformational changes to downstream signalling not established