Regulation of epidermal homeostasis through P2Y₂receptors

Abstract

1 Previous studies have indicated a role for extracellular ATP in the regulation of epidermal homeostasis. Here we have investigated the expression of P2Y 2 receptors by human keratinocytes, the cells which comprise the epidermis. 2 Reverse transcriptase-polymerase chain reaction (RT ± PCR) revealed expression of mRNA for the G-protein-coupled, P2Y 2 receptor in primary cultured human keratinocytes. 3 In situ hybridization studies of skin sections revealed that P2Y 2 receptor transcripts were expressed in the native tissue. These studies demonstrated a striking pattern of localization of P2Y 2 receptor transcripts to the basal layer of the epidermis, the site of cell proliferation. 4 Increases in intracellular free Ca 2+ concentration ([Ca 2+ ] i ) in keratinocytes stimulated with ATP or UTP demonstrated the presence of functional P2Y receptors. 5 In proliferation studies based on the incorporation of bromodeoxyuridine (BrdU), ATP, UTP and ATPgS were found to stimulate the proliferation of keratinocytes. 6 Using a real-time ®re¯y luciferase and luciferin assay we have shown that under static conditions cultured human keratinocytes release ATP. 7 These ®ndings indicate that P2Y 2 receptors play a major role in epidermal homeostasis, and may provide novel targets for therapy of proliferative disorders of the epidermis, including psoriasis.

ATP Activates Regulatory T Cells In Vivo during Contact Hypersensitivity Reactions

“…These elevated levels of ATP in the skin can further be augmented by keratinocytes and endothelial cells, which both have been shown to be a source for ATP (35)(36)(37). Thus, this localized immune reaction is able to produce enough ATP, which may reach the serum causing activation of Tregs in the blood.…”

Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

“…Recently, it has been shown that P2 receptors are expressed in keratinocytes (17,18), but little is known about their physiological significance. During studies to clarify the role of ATP released from keratinocytes, we found that ATP produced IL-6 through P2Y 2 / P2Y 4 receptors in HaCaT keratinocytes (19).…”

Mechanosensitive ATP release from hemichannels and Ca2+ influx through TRPC6 accelerate wound closure in keratinocytes

“…It was reported that mechanosensitive ATP release in keratinocytes primarily auto-stimulates P2Y2 receptors and concomitantly triggers Ca 2+ influx through Ca 2+ -permeable channels (Koizumi et al, 2004;Yoshida et al, 2006;Tsutsumi et al, 2009;Boucher et al, 2010;Azorin et al, 2011;Takada et al, 2012;Ho et al, 2013), which then initiates cell migration, the primary process in the wound healing cascade (Dixon et al, 1999;Burrell et al, 2003;Burrell et al, 2005;Braun, et al, 2006;Boucher et al, 2010). We recently suggested that stretch-induced ATP release and a subsequent Ca 2+ increase mediated by P2Y activation (ATP-Ca 2+ signaling) were involved in wound closure in HaCaT keratinocytes (Takada et al, 2012).…”