Gap junctions are specialized matched membrane domains that contain channels that allow exchange of small molecules including ions, metabolites, and second messengers (e.g., Ca2+ and IP3) between neighboring cells. These channels are necessary for proper development, and genetic linkage analyses have implicated connexins in at least 14 human diseases. The gap junction protein connexin43 (Cx43) is regulated by more than 12 phosphorylation events. The short half-life of Cx43 (~2 h) causes gap junctions to be constantly assembled, remodeled and turned over. Growth factors and wounding can further reduce Cx43's half-life and clear gap junctions from the plasma membrane within an hour in a process we term acute turnover. This proposal focuses on the role that Cx43 phosphorylation plays in gap junction stability and how acute turnover is enhanced in response to growth factors and skin wounding. We propose to: (1). determine if increased gap junction size promotes acute turnover; (2). test whether Src phosphorylation of Cx43 is necessary for GJ internalization and directs the endocytic route, and (3). determine the physiological consequences of Cx43 phosphorylation and gap junction turnover during epidermal wounding.

Public Health Relevance

Cx43 phosphorylation regulates biological responses to growth factor treatment and wound repair. Our research could have a large translational impact since Cx43 is a drug gable target currently being investigated for wound healing uses - the tissue on which we have chosen to focus our research. We hypothesize that more targeted drugs such as kinase activators or inhibitors could be topically applied in a manner dictated by the wound status (i.e., fresh, ulcerated, diabetic, etc.) to yield better healing and reduce the need for amputation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM055632-17A1
Application #
8759795
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Nie, Zhongzhen
Project Start
1997-05-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Laird, Dale W; Lampe, Paul D (2018) Therapeutic strategies targeting connexins. Nat Rev Drug Discov :
Slavi, Nefeli; Toychiev, Abduqodir H; Kosmidis, Stylianos et al. (2018) Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy. Proc Natl Acad Sci U S A 115:E5934-E5943
Laird, Dale W; Naus, Christian C; Lampe, Paul D (2017) SnapShot: Connexins and Disease. Cell 170:1260-1260.e1
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Leybaert, Luc; Lampe, Paul D; Dhein, Stefan et al. (2017) Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications. Pharmacol Rev 69:396-478
Jacobsen, Nicole L; Pontifex, Tasha K; Li, Hanjun et al. (2017) Regulation of Cx37 channel and growth-suppressive properties by phosphorylation. J Cell Sci 130:3308-3321
Crassous, Pierre-Antoine; Shu, Ping; Huang, Can et al. (2017) Newly Identified NO-Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function. J Am Heart Assoc 6:
Egbert, Jeremy R; Uliasz, Tracy F; Shuhaibar, Leia C et al. (2016) Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis. Biol Reprod 94:110

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