Insight into SUCNR1 (GPR91) structure and function

Abstract

SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

Identification and pharmacological characterization of succinate receptor agonists

“…Recently, Roth and Kroeze () proposed that it was the availability of good ligands that made some GPCR popular and not the other way around. The receptor for succinic acid, the succinate receptor, belongs to this category of attractive drug target (Gilissen et al , ) whose pharmacology is poorly defined. Notwithstanding its demonstrated involvement in immune responses and inflammation (Rubic et al , ; Littlewood‐Evans et al , ), retinal angiogenesis (Sapieha et al , ) and regulation of renin release (Toma et al , ; Peti‐Peterdi et al , ), surprisingly few research tools are available and only sparse information about its molecular structure has been published.…”

“…Although it is tempting to speculate that it is the consequence of an activation of succinate receptors, additional experiments are needed (with antagonist or knockout animals) to substantiate the direct link between c ESA‐ and c CPDA‐mediated increase in BP and succinate receptors. The oxoglutarate receptor (OXGR1) and the purinergic P2Y 1 receptor are two GPCRs, most closely related to the succinate receptor (Gilissen et al , ). Although succinate has been shown previously to be unable to activate these two other GPCRs in various assays (He et al , ), further investigation is needed to address the activity of succinic acid and other succinate receptor ligands with regard to these receptors.…”

Krebs cycle rewired for macrophage and dendritic cell effector functions

“…Since the discovery of SUCNR1, the elucidation of the signalling cascades elicited by binding of succinate has begun to emerge . Robben et al .…”

Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

“…SCFA production in the mammalian colon approximately reaches 100 mM per day [50]. SCFA diffuse through the intestinal mucosa, circulate in the bloodstream (via the portal system; at the low-millimolar range), and act on G protein-coupled receptors (GPCR) expressed at the plasma membrane of target cells distributed widely in the mammalian organism [51,52]. Various health promoting effects have been ascribed to specific SCFAs.…”