GPR55 ‐dependent stimulation of insulin secretion from isolated mouse and human islets of L angerhans

Aims The novel cannabinoid receptor GPR55 is expressed by rodent islets and it has been implicated in β‐cell function in response to a range of ligands. This study evaluated the effects of GPR55 ligands on intracellular calcium ([ C a 2+ ] i ) levels and insulin secretion from islets isolated from GPR55 knockout ( GPR55 −/− ) mice, age‐matched wildtype ( WT ) mice and human pancreas. Materials and methods GPR55 expression was determined by Western blotting and fluorescent immunohistochemistry. Changes in [ C a 2+ ] i were measured by F ura‐2 microfluorimetry. Dynamic insulin secretion was quantified by radioimmunoassay following perifusion of isolated islets. RhoA activity was monitored using a R ho binding domain pull down assay. Results Western blotting indicated that MIN6 β‐cells, mouse and human islets express GPR55 and its localization on human β‐cells was demonstrated by fluorescent immunohistochemistry. The pharmacological GPR55 agonist O ‐1602 ( 10 μM ) significantly stimulated [ C a 2+ ] i and insulin secretion from WT mouse islets and these stimulatory effects were abolished in islets isolated from GPR55 −/− mice. In contrast, while the putative endogenous GPR55 agonist lysophosphatidylinositol ( LPI , 5 µ M ) and the GPR55 antagonist cannabidiol ( CBD , 1 µ M ) also elevated [ C a 2+ ] i and insulin secretion, these effects were sustained in islets from GPR55 −/− mice. Stimulatory effects of O ‐1602 on [ C a 2+ ] i and insulin secretion were also observed in experiments using human islets, but O ‐1602 did not activate RhoA in MIN6 β‐cells. Conclusions Our results therefore suggest that GPR55 plays an important role in the regulation of mouse and human islet physiology, but LPI and CBD exert stimulatory effects on islet function by a GPR55 ‐independent pathway(s).