GPR91

GPR91, also known as SUCNR1, is a G protein-coupled receptor that binds extracellular succinate, a metabolite of the tricarboxylic acid cycle. It belongs to the rhodopsin-like GPCR family and transduces signals from metabolic stress to cellular responses. GPR91 was identified as a receptor for succinate in a variety of tissues, highlighting a link between metabolism and signaling.

Expression of GPR91 has been reported in multiple tissues and cell types, including kidney juxtaglomerular cells, retina, adipose tissue, liver, endothelial cells, and various immune cells such as dendritic cells and macrophages. This broad distribution supports roles in both physiological regulation and response to metabolic perturbations.

Signaling operates primarily through Gq/11 proteins, leading to phospholipase C activation, inositol trisphosphate production, and rises in intracellular calcium, with subsequent activation of downstream pathways such as ERK/MAPK. In some contexts, coupling to Gi/o has also been observed, which can modulate cyclic AMP levels. The receptor can influence diverse processes, including renin release in the kidney, angiogenic responses in the retina, and chemotactic or inflammatory responses in immune cells.

Physiological and pathophysiological roles attributed to GPR91 include regulation of blood pressure via renin secretion, contribution to retinal neovascularization under ischemic conditions, and participation in metabolic or inflammatory signaling in adipose tissue and liver. Its activity links cellular metabolic status to tissue-specific responses, with potential implications in hypertension, ischemic retinopathy, obesity-related inflammation, and related disorders.

Clinical and research status: GPR91/SUCNR1 is a focus of study as a potential therapeutic target in conditions involving metabolic stress and inflammation. Selective agonists and antagonists have been developed for research, but clinical applications remain investigational.