GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

Abstract

Succinate receptor GPR91 is one of G protein‐coupled receptors (GPCRs), and is expressed in a variety of cell types and tissues. Succinate is its natural ligand, and its activation represents that an intrinsic metabolic intermediate exerts a regulatory role on many critical life processes involving pathophysiologic mechanisms, such as innate immunity, inflammation, tissue repair, and oncogenesis. With the illustration of 3‐dimensional crystal structure of the receptor and discovery of its antagonists, it is possible to dissect the succinate‐GPR91‐G protein signaling pathways in different cell types under pathophysiological conditions. Deep understanding of the GPR91‐ligand binding mode with various agonists and antagonists would aid in elucidating the molecular basis of a spectrum of chronic illnesses, such as hypertension, diabetes, and their renal and retina complications, metabolic‐associated fatty liver diseases, such as nonalcoholic steatohepatitis and its fibrotic progression, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), age‐related macular degeneration, rheumatoid arthritis, and progressive behaviors of malignancies. With better delineation of critical regulatory role of the succinate‐GPR91 axis in these illnesses, therapeutic intervention may be developed by specifically targeting this signaling pathway with small molecular antagonists or other strategies.

Succinate/IL-1β Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis

“…Succinate, an inflammatory signal, only has a conducting effect in the presence of Sucnr1. Sucnr1/GPR91 refers to a G protein-coupled cell surface sensor in terms of extracellular succinate (26)(27)(28)(29), which is stably expressed on immature Dendritic cells (DCs) and macrophages in immune systems (28). As reported by the cell experiments, Sucnr1 could be stably expressed in HUVECs, thereby creating a pathway for uptaking external succinate.…”

Gemigliptin Alleviates Succinate-Induced Hepatic Stellate Cell Activation by Ameliorating Mitochondrial Dysfunction

“…Although succinate is normally produced in mitochondria, accumulated succinate is released into the extracellular space and acts as a paracrine and endocrine effector by binding its receptor, known as G-protein coupled receptor 91 (GPR91), in HSCs. GPR91 is exclusively expressed in HSCs, and once stimulated by succinate it activates the downstream mitogen-activated protein kinase (MEK1/2) by further promoting the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun [ 7 ]. Subsequently, the expression of nuclear transcription factors and production of α-smooth muscle actin (α-SMA) stimulates the activation, proliferation, and migration of HSCs.…”

4'‑O‑methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway

“…Succinate produces broad pathophysiological effects by binding to the G-protein-coupled receptor 91 (GPR91)/Succinate receptor 1 (SUCNR1). SUCNR1 is expressed in the kidney, liver, heart, retinal cells and other tissues and is involved in regulating blood pressure, inhibiting lipolysis of white fat, forming retinal blood vessels, promoting cardiac hypertrophy and activating hepatic stellate cells (21,22). In a pulmonary arterial hypertension model of pressure overload-induced right ventricular hypertrophy in Sprague-Dawley rats, succinate treatment further aggravated right ventricular hypertrophy, upregulated the right ventricular hypertrophy-related gene ANP and activated PI3K/Akt axis signaling (23).…”