The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

Abstract

Aims Endocannabinoids are lipid mediators involved in the regulation of glucose homeostasis. They interact with the canonical cannabinoid receptors CB 1 and CB 2 , and it is now apparent that some cannabinoid receptor ligands are also agonists at GPR55. Thus, CB 1 antagonists such as SR141716A, also known as rimonabant, and AM251 act as GPR55 agonists in some cell types. The complex pharmacological properties of cannabinoids make it difficult to fully identify the relative importance of CB 1 and GPR55 in the functional effects of SR141716A, and AM251. Here, we determine whether SR141716A and AM251 regulation of mouse and human islet function is through their action as GPR55 agonists. Methods Islets isolated from Gpr55 +/+ and Gpr55 −/− mice and human donors were incubated in the absence or presence of 10 µM SR141716A or AM251, concentrations that are known to activate GPR55. Insulin secretion, cAMP, IP 1 , apoptosis and β-cell proliferation were quantified by standard techniques. Results Our results provide the first evidence that SR141716A and AM251 are not GPR55 agonists in islets, as their effects are maintained in islets isolated from Gpr55 −/− mice. Their signalling through G q-coupled cascades to induce insulin secretion and human β-cell proliferation, and protect against apoptosis in vitro, indicate that they have direct beneficial effects on islet function. Conclusion These observations may be useful in directing development of peripherally restricted novel therapeutics that are structurally related to SR141716A and AM251, and which potentiate glucose-induced insulin secretion and stimulate β-cell proliferation.

High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain

“…This raises the possibility that GPR55 regulates glucose-stimulated insulin secretion. A recent study found no difference between wildtype and GPR55 knockout mice murine isolated islets of Langerhans in their responses to rimonabant ( Ruz-Maldonado et al, 2020 ), which is consistent with our finding that genotype did not affect the effect of rimonabant on et al glucose homeostasis. The authors did not discuss whether glucose-stimulated insulin secretion differed between islets from wild-type and knockout mice.…”

CB1 Activity Drives the Selection of Navigational Strategies: A Behavioral and c-Fos Immunoreactivity Study

“…As an additional complexity in facing ECS, it has to be taken into account that AM251 exhibits significant activity not only at CB 1 as an inverse agonist/antagonist, but also at orphan cannabinoid G-protein-coupled receptor 55 (GPR55) as an agonist [60][61][62][63]. The lack of homology between cannabinoid receptors may explain the differences among CB 1 and GPR55 in the signaling system and downstream cascade.…”

Direct Stimulatory Effects of the CB2 Ligand JTE 907 in Human and Mouse Islets

“…In this context, the endocannabinoid system (ECS) is of particular interest since it was targeted by the cannabinoid (CB) receptor type 1 (CB 1 ) antagonist rimonabant to aid weight loss and improve glycaemic control [ 3 , 4 , 5 ]. The ECS is a cell-signaling network formed by endogenous ligands, named endocannabinoids, their enzymes of synthesis and degradation, and their receptors [ 6 , 7 , 8 , 9 ]. Phospholipid-derived endocannabinoids such as 2-arachidonoylglycerol and anandamide act as activators of the canonical CB 1 and CB 2 receptors [ 6 ].…”

“…Phospholipid-derived endocannabinoids such as 2-arachidonoylglycerol and anandamide act as activators of the canonical CB 1 and CB 2 receptors [ 6 ]. Both receptors belong to the seven-transmembrane G protein-coupled receptor (GPCR) conserved family and they are distributed centrally and peripherally in active metabolic tissues [ 6 , 9 ].…”

“…Several studies have demonstrated that islets express elements of the ECS [ 6 , 8 , 10 , 11 , 12 , 13 , 14 ]. Furthermore, there are reports that cannabinoid receptor ligands can regulate insulin secretion and cell viability [ 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ], which are the desired pathways to be enhanced under conditions of impaired glucose tolerance or T2D [ 1 ]. However, a growing number of studies concerning cannabinoid ligand off-target effects highlight the complex pharmacology surrounding the ECS [ 9 , 15 , 18 , 19 ].…”