An agonist of the cannabinoid-sensing G-protein coupled receptor 55 promotes wound healing and protects against UVB-induced keratinocyte damage.

The use of cannabinoid has been implicated in the treatment of various skin disorders with obscure mechanism of action. This study aimed to investigate the physiological roles of GPR55 in regenerating skin wounds and protecting keratinocyte apoptosis induced by UVB radiation. Here, we found that O1602, a GPR55 agonist, accelerated wound healing in keratinocyte-like HaCaT cells, and this effect was suppressed by pretreatment with inhibitors of protein kinase A (PKA), AMP-activated protein kinase (AMPK), sirtuin-1 (SIRT-1), and extracellular signal-regulated kinase (ERK). Although O1602 treatment promoted keratinocyte proliferation in HaCaT cell line but its proliferative effect did not contribute to enhancing wound healing. Indeed, O1602 upregulated expression of MMP-9, suggesting the stimulation of cell migration. O1602 treatment protected against UVB-induced keratinocyte apoptosis, and this effect was abolished by pretreatment with inhibitors belonging to the same class as that which suppressed the wound-healing response. Furthermore, western blotting analyses revealed that O1602 treatment induced AMPK phosphorylation, and this effect was inhibited by pretreatment of PKA inhibitor. Moreover, O1602 promoted ERK phosphorylation, and this effect was aborted by pretreatment of either AMPK inhibitor or SIRT-1 inhibitor. Enzymatic activation of SIRT-1 induced by O1602 was absent in AMPK inhibitor-pretreated HaCaT cells. Altogether, GPR55 mediates keratinocyte regeneration and exhibits its protective effect against UVB exposure via PKA/AMPK/SIRT-1/ERK-dependent mechanism.