Beyond canonical GPCR: emerging roles of seven transmembrane proteins in metabolic control – insights from GPR180: A review

G protein–coupled receptors (GPCRs) are traditionally defined by their seven-transmembrane (7TM) domain architecture and ability to activate heterotrimeric G proteins. However, accumulating evidence challenges this structure-centric view, revealing a growing class of 7TM proteins that operate through non-canonical mechanisms. GPR180, initially annotated as an orphan GPCR based on predicted 7TM structure, has emerged as a paradigmatic example of this divergence. It lacks demonstrable G protein coupling and instead regulates metabolic function through atypical signalling pathways that influence mitochondrial bioenergetics, lipid handling, and cellular phenotype across multiple metabolic tissues. In adipose tissue, GPR180 controls adipocyte metabolic capacity and thermogenic programming, whereas in the liver, it modulates lipid homeostasis. Importantly, experimental topology analyses reveal inverted membrane orientation, distinguishing GPR180 from bona fide GPCRs despite shared 7TM architecture. Recent structural and functional analyses place GPR180 within the GOST (GOLD-domain 7TM) protein family; here, we propose a metabolically specialized GOST subclass, defined by regulation of mitochondrial bioenergetics and metabolic cell identity rather than classical G protein signalling. Together, these findings argue that GPR180 does not operate as a classical GPCR and highlight the need for functional criteria that extend beyond 7TM architecture when defining receptor identity. More broadly, GPR180 exemplifies how atypical 7TM proteins integrate metabolic state and cellular context to shape signalling output, providing a conceptual framework to systematically identify additional GOST family members with organelle-centred, non-canonical metabolic functions.