There is increasing evidence of the importance of endogenous electric fields in tissue repair and remodeling. Our work has extended the physiological relevance of endogenous electric fields to skin wound healing, demonstrating that DC fields of the magnitude generated immediately upon wounding provide guidance cues for keratinocyte migration. Keratinocytes migrate toward the cathode in DC electric fields of physiological strength, and since the cathodal pole of the field is at the center of the wound, directional migration of keratinocytes is guided to facilitate wound re-epithelialization. We now have developed the tools and resources to dissect the mechanisms involved in this important aspect of wound healing, the application of which may lead to novel therapeutic approaches. One of the highlights of our fmdings has been the demonstration of a requirement for epidermal growth factor receptor (EGFR) kinase activation and its re-localization to the cathodal face of the cell. This prompts us to propose two specific issues. First, how is the EGF receptor localized to the cathodal face of the cell? We will determine if DC electric field application directs localized cathodal exocytosis of EGF receptor-carrying vesicles. Localized exocytosis would add membrane at the cathodal face of the cell, allowing lamellipodial extension and directional movement, and we will examine cell membrane tension at cathodal and anodal facing ends of the cell to address this question. Second, because the galvanotaxis response is dependent on EGF receptor kinase activity, we will dissect the upstream pathways for its localized activation in DC fields. Since reactive oxygen species (ROS) can activate EGFR, we will determine if DC fields generate ROS polarized to the cathodal cell membrane. The effects of up or down-regulation of ROS on directional motility and EGFR phosphorylation will be investigated. Moreover, our pilot data implicate the G protein-coupled beta2-adrenergic receptor (B2AR), in keratinocyte migration, so transactivation of the EGFR through DC field-induced activation of the B2AR will be examined. Mediation of directional migration by selective association of B2AR with either the GTP-binding Gi or Gs proteins will be determined. We submit that multiple pathways may converge upon the EGFR to initiate directional migration in response to the DC field. Dissection of the pathways governing galvanotaxis will likely provide a paradigm for understanding the basic cell function of directional migration in chemotaxis and will ultimately direct us to potential therapeutic interventions to enhance wound healing.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Baker, Carl
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University of California Davis
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Sivamani, Raja K; Shi, Biao; Griffiths, Elizabeth et al. (2014) Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes. J Invest Dermatol 134:2258-2266
Yang, Hsin-Ya; Charles, Roch-Philippe; Hummler, Edith et al. (2013) The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes. J Cell Sci 126:1942-51
Pullar, Christine E; Le Provost, Gabrielle S; O'Leary, Andrew P et al. (2012) ?2AR antagonists and ?2AR gene deletion both promote skin wound repair processes. J Invest Dermatol 132:2076-84
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Liu, Wei; Hsu, Daniel K; Chen, Huan-Yuan et al. (2012) Galectin-3 regulates intracellular trafficking of EGFR through Alix and promotes keratinocyte migration. J Invest Dermatol 132:2828-37
Sivamani, Raja K; Schwartz, Michael P; Anseth, Kristi S et al. (2011) Keratinocyte proximity and contact can play a significant role in determining mesenchymal stem cell fate in human tissue. FASEB J 25:122-31
Steenhuis, P; Huntley, R E; Gurenko, Z et al. (2011) Adrenergic signaling in human oral keratinocytes and wound repair. J Dent Res 90:186-92
Lulevich, Valentin; Yang, Hsin-ya; Isseroff, R Rivkah et al. (2010) Single cell mechanics of keratinocyte cells. Ultramicroscopy 110:1435-42
Sivamani, Raja K; Porter, Scott M; Isseroff, R Rivkah (2009) An epinephrine-dependent mechanism for the control of UV-induced pigmentation. J Invest Dermatol 129:784-7
Sivamani, Raja K; Pullar, Christine E; Manabat-Hidalgo, Catherine G et al. (2009) Stress-mediated increases in systemic and local epinephrine impair skin wound healing: potential new indication for beta blockers. PLoS Med 6:e12

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