TY - JOUR
T1 - Two olfactory receptors—OR2A4/7 and OR51B5—differentially affect epidermal proliferation and differentiation
AU - Tsai, Teresa
AU - Veitinger, Sophie
AU - Peek, Irina
AU - Busse, Daniela
AU - Eckardt, Josephine
AU - Vladimirova, Dilyana
AU - Jovancevic, Nikolina
AU - Wojcik, Sebastian
AU - Gisselmann, Günter
AU - Altmüller, Janine
AU - Ständer, Sonja
AU - Luger, Thomas
AU - Paus, Ralf
AU - Cheret, Jeremy
AU - Hatt, Hanns
N1 - Funding Information:
We thank F. M??ler, E. Makic and P. Kudella for excellent technical assistance. We thank the Genotype-Tissue Expression (GTEx) Project which was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract HHSN268201000029C. The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina ? Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810) and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 05/03/15.
Publisher Copyright:
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Olfactory receptors (ORs), which belong to the G-protein coupled receptor family, are expressed in various human tissues, including skin. Cells in non-olfactory tissues tend to express more than one individual OR gene, but function and interaction of two or more ORs in the same cell type has only been marginally analysed. Here, we revealed OR2A4/7 and OR51B5 as two new ORs in human skin cells and identified cyclohexyl salicylate and isononyl alcohol as agonists of these receptors. In cultured human keratinocytes, both odorants induce strong Ca2+ signals that are mediated by OR2A4/7 and OR51B5, as demonstrated by the receptor knockdown experiments. Activation of corresponding receptors induces a cAMP-dependent pathway. Localization studies and functional characterization of both receptors revealed several differences. OR2A4/7 is expressed in suprabasal keratinocytes and basal melanocytes of the epidermis and influences cytokinesis, cell proliferation, phosphorylation of AKT and Chk-2 and secretion of IL-1. In contrast, OR51B5 is exclusively expressed in suprabasal keratinocytes, supports cell migration and regeneration of keratinocyte monolayers, influences Hsp27, AMPK1 and p38MAPK phosphorylation and interestingly, IL-6 secretion. These findings underline that different ORs perform diverse functions in cutaneous cells, and thus offering an approach for the modulated treatment of skin diseases and wound repair.
AB - Olfactory receptors (ORs), which belong to the G-protein coupled receptor family, are expressed in various human tissues, including skin. Cells in non-olfactory tissues tend to express more than one individual OR gene, but function and interaction of two or more ORs in the same cell type has only been marginally analysed. Here, we revealed OR2A4/7 and OR51B5 as two new ORs in human skin cells and identified cyclohexyl salicylate and isononyl alcohol as agonists of these receptors. In cultured human keratinocytes, both odorants induce strong Ca2+ signals that are mediated by OR2A4/7 and OR51B5, as demonstrated by the receptor knockdown experiments. Activation of corresponding receptors induces a cAMP-dependent pathway. Localization studies and functional characterization of both receptors revealed several differences. OR2A4/7 is expressed in suprabasal keratinocytes and basal melanocytes of the epidermis and influences cytokinesis, cell proliferation, phosphorylation of AKT and Chk-2 and secretion of IL-1. In contrast, OR51B5 is exclusively expressed in suprabasal keratinocytes, supports cell migration and regeneration of keratinocyte monolayers, influences Hsp27, AMPK1 and p38MAPK phosphorylation and interestingly, IL-6 secretion. These findings underline that different ORs perform diverse functions in cutaneous cells, and thus offering an approach for the modulated treatment of skin diseases and wound repair.
KW - HaCaT
KW - ectopic expression
KW - keratinocytes
KW - proliferation
KW - wound healing
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U2 - 10.1111/exd.13132
DO - 10.1111/exd.13132
M3 - Article
C2 - 27315375
AN - SCOPUS:85007107570
VL - 26
SP - 58
EP - 65
JO - Experimental Dermatology
JF - Experimental Dermatology
SN - 0906-6705
IS - 1
ER -