Beta-adrenergic receptor agonists delay while antagonists accelerate epithelial wound healing: evidence of an endogenous adrenergic network within the corneal epithelium.
Wound healing is a complex and well-orchestrated biological process. Corneal epithelial cells (CECs) must respond quickly to trauma to rapidly restore barrier function and protect the eye from noxious agents. They express a high level of beta2-adrenergic receptors but their function is unknown. Here, we report the novel finding that they form part of a regulatory network in the corneal epithelium, capable of modulating corneal epithelial wound repair. Beta-adrenergic receptor agonists delay CEC migration via a protein phosphatase 2A-mediated mechanism and decrease both electric field-directed migration and corneal wound healing. Conversely, beta-adrenergic receptor antagonists accelerate CEC migration, enhance electric field-mediated directional migration, and promote corneal wound repair. We demonstrate that CECs express key enzymes required for epinephrine (beta-adrenergic receptor agonist) synthesis in the cytoplasm and can detect epinephrine in cell extracts. We propose that the mechanism for the pro-motogenic effect of the beta-adrenergic antagonist is blockade of the beta2-adrenergic receptor preventing autocrine catecholamine binding. Further investigation of this network will improve our understanding of one of the most frequently prescribed class of drugs.
Pullar
Christine E
CE
Department of Dermatology, University of California Davis, Davis, California, USA. cp161@le.ac.uk
Zhao
Min
M
Song
Bing
B
Pu
Jin
J
Reid
Brian
B
Ghoghawala
Shahed
S
McCaig
Colin
C
Isseroff
R Rivkah
RR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D004566:Electrodes; D004837:Epinephrine / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D019573:Epithelium, Corneal / Q000187:drug effects* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2; D014945:Wound Healing / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D004837:Epinephrine