The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions

Abstract

The succinate receptor (also known as GPR91) is a G protein-coupled receptor that is closely related to the family of P2Y purinoreceptors. It is expressed in a variety of tissues, including blood cells, adipose tissue, the liver, retina, and kidney. In these tissues, this receptor and its ligand succinate have recently emerged as novel mediators in local stress situations, including ischemia, hypoxia, toxicity, and hyperglycemia. Amongst others, the succinate receptor is involved in recruitment of immune cells to transplanted tissues. Moreover, it was shown to play a key role in the development of diabetic retinopathy. However, most prominently, the role of locally increased succinate levels and succinate receptor activation in the kidney, stimulating the systemic and local renin-angiotensin system, starts to unfold: the succinate receptor is a key mediator in the development of hypertension and possibly fibrosis in diabetes mellitus and metabolic syndrome. This makes the succinate receptor a promising drug target to counteract or prevent cardiovascular and fibrotic defects in these expanding disorders. Recent development of SUCNR1-specific antagonists opens novel possibilities for research in models for these disorders and may eventually provide novel opportunities for the treatment of patients.

Keywords: GPCR; GPR91; SUCNR1; diabetes mellitus; oxidative stress; renal disease; rennin; succinate.

Figure 1

Sequence alignment of human, rat, and mouse SUCNR1. Yellow residues are conserved between species. Predicted transmembrane (TM) domains I–VII are indicated by black lines. Residues important for succinate binding (Arg99, His103, Arg252, and Arg281) are indicated with red arrows.

Figure 2

Generation of succinate in mitochondria. (A) Succinate is an intermediate in the citric acid cycle, and is converted by succinate dehydrogenase (also called complex II) to fumarate. When high H⁺ gradients over the inner membrane are present, or when the oxygen pressure is low, complex I, II, III, and IV will be inhibited, leading to accumulation of succinate. (B) Overview of the citric acid cycle under normal physiological conditions. (C) Cellular stress such as hypoxia may affect normal functioning of the citric acid cycle and induce a part of the cycle to run in reverse, ultimately leading to increased succinate production. See text for more details and references.

Figure 3

Signaling of SUCNR1 in the kidney. (A) Signaling in the juxtaglomerular apparatus. SUCNR1 is expressed in several parts of the nephron (indicated in red), where it contributes to renin release from the JGA (see inset on the right). Succinate receptor activation on macula densa (MD) cells or on endothelial cells of the afferent arteriole (AA) induce the release of prostaglandin E2 (PGE2) and nitric oxide (NO), which trigger the release of renin form the granular cells of the juxtaglomerular apparatus (JGA). Additional abbreviations: EA, efferent arteriole; cTAL, cortical thick ascending limb. (B) Intracellular signaling. In tubular cells, diabetes mellitus, ischemia/reperfusion injury, or oxidatives stress affect the functioning of the mitochondria, resulting in the release of succinate into the cytoplasm and eventually to the extracellular environment. There, it can bind to SUCNR1 on the cell surface. This triggers a signaling cascade that eventually leads to the secretion of nitric oxide (NO) and prostaglandin E2 (PGE2). These signaling molecules will subsequently promote the release of renin from the JGA as described under (A). Abbreviations: PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PKC, protein kinase C; pERK1/2, phosphorylated extracellularly regulated kinase 1/2; COX, cyclo-oxogenase, eNOS, endothelial nitric oxide synthase.

Figure 4

Structure of SUCNR1 ligands. From left to right: succinic acid, compound “4g,” compound “5g,” and compound “7e.” Structures were derived from (Bhuniya et al., 2011).