G protein coupled receptor 18: A potential role for endocannabinoid signaling in metabolic dysfunction

Abstract

Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels. Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression. These cannabinoid receptors are part of a large family of G protein coupled receptors (GPCRs). GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal, and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus. Obesity is considered a state of chronic low-grade inflammation elicited by an immunological response. Interestingly, the newly deorphanized GPCR (GPR18), which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function. In this review, the current scientific knowledge on GPR18 is explored including its localization, signaling pathways, and pharmacology. Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described. Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.

The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

“…In fact, IL-6 is one of the primary mediators of low-grade inflammation in obesity (3) and both CXCL-1 as well as IL-5 have been found to be altered in prediabetes (6,38). There are some evidence pointing at Abn-CBD as a modulator of the inflammatory response (19) and the two main G-protein coupled receptors (GPCRs) that so far have been related to Abn-CBD effects, i.e., GPR18 and GPR55, have been widely involved in inflammation and related processes (39,40). Comparable to our data, the GPR55 agonist O-1602 significantly reduced the levels of IL-6 both in plasma and pancreas tissue in mice with cerulein-induced pancreatitis (34).…”

LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

“…However, Abn‐CBD induced increased [Ca 2+ ] i in islets from GPR55 −/− mice, consistent with the insulin secretion data and suggesting that it acts through another receptor. A possible candidate is GPR18, which is activated by Abn‐CBD, expressed by islets, and it has been reported that GPR18 activation is associated with transient elevation of [Ca 2+ ] i. Nothing is known about the functional role of GPR18 in islets, but it has been reported that the GPR18 agonist N‐arachidonylglycine promotes elevations in β‐cell [Ca 2+ ] i and potentiates insulin secretion from rat islets …”

The Effect of Chronic Activation of the Novel Endocannabinoid Receptor GPR18 on Myocardial Function and Blood Pressure in Conscious Rats

“…It is important to consider possible biased agonism for O-1918 at GPR18 because O-1918 increased calcium mobilization and mitogen activated protein kinase (MAPK) activity in GPR18-transfected HEK293 cells 31 . However, the possibility that these effects of O-1918 are tissue specific, reinforces the need for more studies to address this issue 32 .…”