ORAI1 Ca(2+) channels control endothelin-1-induced mitogenesis and melanogenesis in primary human melanocytes.
UV radiation of the skin triggers keratinocytes to secrete endothelin-1 (ET-1) that binds to endothelin receptors on neighboring melanocytes. Melanocytes respond with a prolonged increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), which is necessary for proliferation and melanogenesis. A major fraction of the Ca(2+) signal is caused by entry through Ca(2+)-permeable channels of unknown identity in the plasma membrane. ORAI Ca(2+) channels are molecular determinants of Ca(2+) release-activated Ca(2+) (CRAC) channels and are expressed in many tissues. Here, we show that ORAI1-3 and their activating partners stromal interaction molecules 1 and 2 (STIM1 and STIM2) are expressed in human melanocytes. Although ORAI1 is the predominant ORAI isoform, STIM2 mRNA expression exceeds STIM1. Inhibition of ORAI1 by 2-aminoethoxydiphenyl borate (2-APB) or downregulation of ORAI1 by small interfering RNA (siRNA) reduced Ca(2+) entry and CRAC current amplitudes in activated melanocytes. In addition, suppression of ORAI1 caused reduction in the ET-1-induced cellular viability, melanin synthesis, and tyrosinase activity. Our results imply a role for ORAI1 channels in skin pigmentation and their potential involvement in UV-induced stress responses of the human skin.
Department of Dermatology, Venerology and Allergology, University Hospital of the Saarland, Homburg, Germany. hedwig.stanisz@uks.eu
Hedwig
H
Stanisz
Alexandra
A
Stark
Tatiana
T
Kilch
Eva C
EC
Schwarz
Cornelia S L
CS
Müller
Christine
C
Peinelt
Markus
M
Hoth
Barbara A
BA
Niemeyer
Thomas
T
Vogt
Ivan
I
Bogeski
D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D000071741:ORAI2 Protein; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2
D001896:Boron Compounds; D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D019332:Endothelin-1; D008543:Melanins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D000071741:ORAI2 Protein; C514506:ORAI2 protein, human; C522867:Orai3 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium