Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

Abstract

Abstract. Insulin secretion with respect to pH environments has been investigated for a long time but its mechanism remains largely unknown. Extracellular pH is usually maintained at around 7.4 and, its change has been thought to occur in non-physiological situations. Acidification takes place under ischemic and inflammatory microenvironments, where stimulation of anaerobic glycolysis results in the production of lactic acid. In addition to ionotropic ion channels, such as transient receptor potential V1 (TRPV1) and acid-sensing ion channels (ASICs), metabotropic proton-sensing G proteincoupled receptors (GPCRs) have also been identified recently as proton-sensing machineries. While ionotropic ion channels usually sense strong acidic pH, proton-sensing GPCRs sense pH of 7.6 to 6.0 and have been shown to mediate a variety of biological actions in neutral and mildly acidic pH environments. Studies with receptor knockout mice have revealed that proton-sensing receptors, including ovarian cancer G protein-coupled receptor 1 (OGR1), a proton-sensing GPCRs, play a role in the regulation of insulin secretion and glucose metabolism under physiological conditions. Small molecule 3,5-disubstituted isoxazoles have recently been identified as OGR1 agonists working at neutral pH and have been shown to stimulate pancreatic β-cell differentiation and insulin synthesis. Thus, proton-sensing OGR1 may be an important player for insulin secretion and a potential target for improving β-cell function.

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

“…Confoundingly, studies with GPR68 knockout (KO) mice uncovered only modest changes in these functions 21,16,22 . Although GPR68 has been reported to be activated by a family of isoxazoles 15 , their weak activity appears to be non-specific 23,24 and could not be reproduced ( Results ). Thus, though GPR68 may have multiple roles, few of them are well-characterized by knockout and none are known in the CNS, where it is most highly expressed.…”

Decreased extracellular pH inhibits osteogenesis through proton-sensing GPR4-mediated suppression of yes-associated protein

“…A group of G-protein-coupled receptors (GPCRs), including GPR412, GPR65 (TDAG8)13, GPR68 (OGR1)14 and GPR132 (G2A)15, have been identified as proton-sensing machineries that can be activated with increases in the proton concentration. GPR68 is usually coupled with Gq/11 and activates phospholipase C (PLC)/Ca 2+ signaling, and GPR4, GPR65 and GPR132 typically activate the adenylyl cyclase/cAMP/PKA pathway through Gs proteins1416. All of these GPCRs can also induce the activation of Rho signaling via G 12/13 1416.…”

Inhibition of interleukin‐1β production by extracellular acidification through the TDAG8/cAMP pathway in mouse microglia

“…; Mogi et al . ; Okajima ). For example, extracellular acidification induces Ca 2+ mobilization in association with phospholipase C activation through OGR1 (Ludwig et al .…”

“…Recent studies revealed that OGR1 family G-proteincoupled receptors (GPCRs), including OGR1, GPR4, G2A, and TDAG8, which have previously been proposed as receptors for lysolipids, sense extracellular protons, resulting in the stimulation of intracellular signaling pathways Seuwen et al 2006;Mogi et al 2013;Okajima 2013). For example, extracellular acidification induces Ca 2+ mobilization in association with phospholipase C activation through OGR1 (Ludwig et al 2003;Mogi et al 2005), activation of the Rho-signaling pathway through G2A (Murakami et al 2004), and stimulation of cAMP accumulation and the Rho-signaling pathway through TDAG8 (Wang et al 2004;Ishii et al 2005;Radu et al 2005;Hikiji et al 2013) and GPR4 (Ludwig et al 2003;Tobo et al 2007;Liu et al 2010).…”