title: A synthetic sandalwood odorant induces wound-healing processes in human keratinocytes via the olfactory receptor OR2AT4.
abstract: As the outermost barrier of the body, the skin is exposed to multiple environmental factors, including temperature, humidity, mechanical stress, and chemical stimuli such as odorants that are often used in cosmetic articles. Keratinocytes, the major cell type of the epidermal layer, express a variety of different sensory receptors that enable them to react to various environmental stimuli and process information in the skin. Here we report the identification of a novel type of chemoreceptors in human keratinocytes, the olfactory receptors (ORs). We cloned and functionally expressed the cutaneous OR, OR2AT4, and identified Sandalore, a synthetic sandalwood odorant, as an agonist of this receptor. Sandalore induces strong Ca(2+) signals in cultured human keratinocytes, which are mediated by OR2AT4, as demonstrated by receptor knockdown experiments using RNA interference. The activation of OR2AT4 induces a cAMP-dependent pathway and phosphorylation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinases (p38 MAPK). Moreover, the long-term stimulation of keratinocytes with Sandalore positively affected cell proliferation and migration, and regeneration of keratinocyte monolayers in an in vitro wound scratch assay. These findings combined with our studies on human skin organ cultures strongly indicate that the OR 2AT4 is involved in human keratinocyte re-epithelialization during wound-healing processes.
authors.affiliation: Department of Cellphysiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Busse
authors.affiliation: Department of Cellphysiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kudella
authors.affiliation: Department of Cellphysiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Nana-Maria
authors.initials: NM
authors.lastname: Grüning
authors.affiliation: Department of Cellphysiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Gisselmann
authors.affiliation: Department of Dermatology, Competence Centre Chronic Pruritus, University Hospital Münster, Münster, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Ständer
authors.affiliation: University Hospital Münster, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Luger
authors.affiliation: Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobsen
authors.affiliation: Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Steinsträßer
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University Hospital Münster, Münster, Germany.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Gkogkolou
authors.affiliation: Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, Department of Dermatology, University Hospital Münster, Münster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Department of Cellphysiology, Ruhr-University Bochum, Bochum, Germany. Electronic address: hanns.hatt@rub.de.
authors.forename: Hanns
authors.initials: H
authors.lastname: Hatt
authors.affiliation: Department of Cellphysiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Benecke
mesh_terms: D002118:Calcium / Q000737:chemistry; D002465:Cell Movement; D049109:Cell Proliferation; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009812:Odorants; D018034:Olfactory Receptor Neurons / Q000378:metabolism; D034622:RNA Interference; D018035:Receptors, Odorant / Q000378:metabolism*; D032123:Santalum / Q000737:chemistry*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D014945:Wound Healing
chemical_list: C000595261:OR2AT4 protein, human; D018035:Receptors, Odorant; D002118:Calcium