title: Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes.
abstract: Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrenergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression levels of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine-N-methyltransferase were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, tyrosine hydroxylase, and phenylethanolamine-N-methyltransferase expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR-binding affinity remained depressed even after its expression returned to prewounding levels. Keratinocyte-derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR-selective antagonist ICI-118,551 but not with B1AR-selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound-edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine-related effects in the wound are warranted.
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA. Electronic address: rksivamani@ucdavis.edu.
authors.forename: Raja K
authors.initials: RK
authors.lastname: Sivamani
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Griffiths
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA.
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Vu
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA; Department of Dermatology, Veterans Affairs Medical Center, Mather, California, USA.
authors.forename: Hadar A
authors.initials: HA
authors.lastname: Lev-Tov
authors.affiliation: Department of Podiatry, Veterans Affairs Medical Center, Mather, California, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Dahle
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Chigbrow
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA.
authors.forename: Thi Dinh
authors.initials: TD
authors.lastname: La
authors.affiliation: Department of Biological Sciences, California State University, Sacramento, California, USA.
authors.forename: Chelcy
authors.initials: C
authors.lastname: Mashburn
authors.affiliation: Department of Biological Sciences, California State University, Sacramento, California, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Peavy
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California, USA; Department of Dermatology, Veterans Affairs Medical Center, Mather, California, USA. Electronic address: rrisseroff@ucdavis.edu.
authors.forename: R Rivkah
authors.initials: RR
authors.lastname: Isseroff
mesh_terms: D000208:Acute Disease; D000368:Aged; D002395:Catecholamines / Q000096:biosynthesis*; D002465:Cell Movement; D002478:Cells, Cultured; D004837:Epinephrine / Q000032:analysis; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008875:Middle Aged; D009638:Norepinephrine / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000293:injuries*
chemical_list: D002395:Catecholamines; D018343:Receptors, Adrenergic, beta-2; D009638:Norepinephrine; D004837:Epinephrine