Moran Brian M, Flatt Peter R, McKillop Aine M
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
Acta Diabetol. 2016 Apr;53(2):177-88. doi: 10.1007/s00592-015-0826-9. Epub 2016 Jan 6.
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.
G蛋白偶联受体（GPCRs）在细胞信号传导中起关键作用，控制着免疫、生长、细胞分化、神经通路和激素分泌等许多过程。脂肪酸激动剂越来越被认为在通过刺激胰岛和胃肠道GPCRs调节葡萄糖稳态中起关键作用。下游细胞信号传导导致胰岛和肠内分泌细胞的生物合成、分泌、增殖和抗凋亡途径的调节。GPR40和GPR120被长链脂肪酸（>C12）激活，这两种受体都与激活Ca(2+)依赖性途径的Gαq亚基偶联。GPR41和GPR43被短链脂肪酸（C2-C5）刺激，激活后导致与Gαi结合，抑制腺苷酸环化酶途径，减少cAMP产生。此外，GPR43也与Gαq亚基偶联，增加细胞内Ca(2+)并激活磷脂酶C。GPR55对大麻素内源性激动剂（内源性大麻素）和非大麻素脂肪酸具有特异性，它与Gα12/13和Gαq蛋白偶联，导致细胞内Ca(2+)增加、细胞外信号调节激酶1/2（ERK）磷酸化和Rho激酶激活。GPR119被脂肪酸乙醇酰胺激活，并利用依赖于蛋白激酶A的腺苷酸环化酶途径与Gαs结合。目前的研究表明，GPCR疗法可能在不久的将来被批准用于临床。本综述重点关注临床前糖尿病研究中，参与葡萄糖稳态的胰岛和肠内分泌细胞上GPCRs信号传导和调节的最新进展。
