Study on a Functional Role of GPR39 in Keratinocytes

Abstract

GPR39, an orphan G-protein-coupled receptor (GPCR), is widely expressed across various tissues and has been implicated in promoting keratinocyte proliferation in the skin. However, studies on its signaling pathways and specific functions in this tissue are limited. In this study, we investigated the role of GPR39 in keratinocyte proliferation using the HaCaT cell line and a peptide agonist, GJ39A, targeting GPR39. We first observed that GJ39A treatment increased intracellular calcium levels, and BrdU assays confirmed that GJ39A promoted keratinocyte proliferation. Further, using various inhibitors, we determined that this proliferation occurred via the PLC-Ca2+-CaMKII-Raf-MEK-ERK signaling pathway. In addition, GJ39A treatment increased the expression of Cyclin D1, a key regulator of cell cycle progression, as well as the expression levels of tight junction proteins occludin and ZO-1, which are essential for skin barrier function. Finally, we observed that GPR39 activation enhanced keratinocyte wound closure in an in vitro scratch model. Additionally, complementary Transwell assays confirmed that GJ39A treatment significantly increased HaCaT cell migration, reinforcing the findings from the scratch model. These findings suggest that GPR39 plays a critical role in keratinocyte proliferation and skin tissue repair, potentially promoting wound healing through Ca2+-dependent signaling pathways.