G protein-coupled receptors: signalling and regulation by lipid agonists for improved glucose homoeostasis

Abstract

G protein-coupled receptors (GPCRs) play a pivotal role in cell signalling, controlling many processes such as immunity, growth, cellular differentiation, neurological pathways and hormone secretions. Fatty acid agonists are increasingly recognised as having a key role in the regulation of glucose homoeostasis via stimulation of islet and gastrointestinal GPCRs. Downstream cell signalling results in modulation of the biosynthesis, secretion, proliferation and anti-apoptotic pathways of islet and enteroendocrine cells. GPR40 and GPR120 are activated by long-chain fatty acids (>C12) with both receptors coupling to the Gαq subunit that activates the Ca(2+)-dependent pathway. GPR41 and GPR43 are stimulated by short-chain fatty acids (C2-C5), and activation results in binding to Gαi that inhibits the adenylyl cyclase pathway attenuating cAMP production. In addition, GPR43 also couples to the Gαq subunit augmenting intracellular Ca(2+) and activating phospholipase C. GPR55 is specific for cannabinoid endogenous agonists (endocannabinoids) and non-cannabinoid fatty acids, which couples to Gα12/13 and Gαq proteins, leading to enhancing intracellular Ca(2+), extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and Rho kinase. GPR119 is activated by fatty acid ethanolamides and binds to Gαs utilising the adenylate cyclase pathway, which is dependent upon protein kinase A. Current research indicates that GPCR therapies may be approved for clinical use in the near future. This review focuses on the recent advances in preclinical diabetes research in the signalling and regulation of GPCRs on islet and enteroendocrine cells involved in glucose homoeostasis.

Deletion of Gpr55 Results in Subtle Effects on Energy Metabolism, Motor Activity and Thermal Pain Sensation

“…These multiple putative clinical indications suggest the existence of comprehensive and complex signalling systems for endogenous cannabinoid molecules (endocannabinoids) in peripheral tissues as well as in the central nervous system (CNS). GPCR′s identified that are activated by endocannabinoids, include the cannabinoid receptor 1 (CB1) [2, 3], 2 (CB2) [4], TRPV1 [5], GPR18 [6] GPR119 [7] and GPR55 [8]. …”

Regulator of G‐protein signaling Gβ5‐R7 is a crucial activator of muscarinic M3 receptor‐stimulated insulin secretion

“…Secretory activity of the endocrine pancreas is tuned by various hormones and neurotransmitters, many of which signal through GPCRs. Gq/11-and Gs-coupled receptors promote glucose-stimulated insulin release by b cells, whereas Gi-coupled receptors exert an inhibitory effect (1). Regulation of b cells also involves ion channels, protein kinases, the cytoskeleton, and secretory machinery, and this intricate network is still far from being understood.…”

A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress

“…Indeed, it is likely that FFA-stimulated JNK activation may occur by more than one mechanism in vivo , possibly in a cell-type and context specific manner. These potential mechanisms include: 1) the FFA-induced endoplasmic reticulum unfolded protein response (Fu et al, 2012); 2) FFA ligand binding to G protein coupled receptors (Alvarez-Curto and Milligan, 2016; Moran et al, 2016); 3) FFA metabolism and accumulation of signaling lipids, including diacylglycerol, ceramide, and sphingosine-1-phosphate (Hu et al, 2009; Montell et al, 2001; Schmitz-Peiffer et al, 1999); 4) FFA-stimulated NBR1-MEKK3 signaling (Hernandez et al, 2014); and 5) FFA-stimulated lipid raft signaling (Holzer et al, 2011). It is also possible that FFA causes JNK activation as part of a generalized lipotoxic stress response (Neuschwander-Tetri, 2010).…”