PGE(2) is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation.
Prostaglandins activate signalling pathways involved in growth, differentiation and apoptosis. Prostaglandin E(2) (PGE(2)) is released by keratinocytes following ultraviolet irradiation (UVR) and stimulates the formation of dendrites in melanocytes. We show that multiple irradiations of human melanocytes with UVR-activated cPLA(2), the rate-limiting enzyme in eicosanoid synthesis and stimulated PGE(2) secretion. PGE(2) increased cAMP production, tyrosinase activity and proliferation in melanocytes. PGE(2) binds to four distinct G-protein coupled receptors (EP(1-4)). We show that PGE(2) stimulates EP(4) receptor signalling in melanocytes, resulting in cAMP production. Conversely, PGE(2) also stimulated the EP(3) receptor in melanocytes, resulting in lowered basal cAMP levels. These data suggest that relative levels or activity of these receptors controls effects of PGE(2) on cAMP in melanocytes. The data are the first to identify PGE(2) as an UVR-inducible autocrine factor for melanocytes. These data also show that PGE(2) activates EP(3) and EP(4) receptor signalling, resulting in opposing effects on cAMP production, a critical signalling pathway that regulates proliferation and melanogenesis in melanocytes.
Starner
Renny J
RJ
McClelland
Lindy
L
Abdel-Malek
Zalfa
Z
Fricke
Alex
A
Scott
Glynis
G
D019898:Autocrine Communication / Q000528:radiation effects; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction; D014466:Ultraviolet Rays / Q000009:adverse effects*
C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone