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 via phosphorylation and its interactions with other proteins. This proposal focuses on the role that these two regulatory processes play and interplay in vivo to affect tissue development and function. We will examine the role Cx43 regulation plays during fundamental biological processes such as in the heart during ischemia, tachycardia and preconditioning, in skin during wound repair, and in the eye during development. We propose to (1) determine the consequences of specific Cx43 phosphorylation events on Cx43 function. (2) characterize changes in Cx43 phosphorylation and function in skin and heart in response to conditions such as wounding and hypoxia/ischemia., and (3) investigate the in vivo role of Cx43 phosphorylation in skin, heart, ovary, and eye at different developmental stages using """"""""knock-in"""""""" mice expressing phosphorylation site mutants of Cx43. Understanding the linkage of changes in Cx43 phosphorylation to the exquisite control of fundamental biological events is in itself important but given that drugs to affect Cx43-related cardiac function and Cx43 anti-sense gels to speed wound healing are being tested in humans, we need to fully define these medically important biological events to better understand their implications and opportunities for patient treatment.

Public Health Relevance

We propose to investigate the linkage of changes in the phosphorylation of the gap junction protein connexin43 and gap junctional communication to the exquisite control of cellular proliferation and migration during development, cardiac stress, and wound healing. Since Cx43 anti-sense treatments for wound healing and drugs to affect Cx43-related cardiac function are currently being tested in humans, our results will help us to better understand current drug implications for patient treatment and may lead to better alternatives.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055632-16
Application #
8404055
Study Section
Intercellular Interactions (ICI)
Program Officer
Deatherage, James F
Project Start
1997-05-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
16
Fiscal Year
2013
Total Cost
$359,322
Indirect Cost
$150,100
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Jabr, Rita I; Hatch, Fiona S; Salvage, Samantha C et al. (2016) Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction. Pflugers Arch 468:1945-1955

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