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.
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.
|Solan, Joell L; Lampe, Paul D (2014) Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Lett 588:1423-9|
|Dunn, Clarence A; Lampe, Paul D (2014) Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size. J Cell Sci 127:455-64|
|Chen, Steven C; Kennedy, Brian K; Lampe, Paul D (2013) Phosphorylation of connexin43 on S279/282 may contribute to laminopathy-associated conduction defects. Exp Cell Res 319:888-96|
|Sakurai, Takashi; Tsuchida, Mariko; Lampe, Paul D et al. (2013) Cardiomyocyte FGF signaling is required for Cx43 phosphorylation and cardiac gap junction maintenance. Exp Cell Res 319:2152-65|
|Li, Dan; Sekhon, Poonampreet; Barr, Kevin J et al. (2013) Connexins and steroidogenesis in mouse Leydig cells. Can J Physiol Pharmacol 91:157-64|
|Marquez-Rosado, Lucrecia; Singh, Deepika; Rincon-Arano, Hector et al. (2012) CASK (LIN2) interacts with Cx43 in wounded skin and their coexpression affects cell migration. J Cell Sci 125:695-702|
|Dunn, Clarence A; Su, Vivian; Lau, Alan F et al. (2012) Activation of Akt, not connexin 43 protein ubiquitination, regulates gap junction stability. J Biol Chem 287:2600-7|
|Boassa, Daniela; Solan, Joell L; Papas, Adrian et al. (2010) Trafficking and recycling of the connexin43 gap junction protein during mitosis. Traffic 11:1471-86|
|del Castillo, Francisco J; Cohen-Salmon, Martine; Charollais, Anne et al. (2010) Consortin, a trans-Golgi network cargo receptor for the plasma membrane targeting and recycling of connexins. Hum Mol Genet 19:262-75|
|Qu, Jiaxiang; Volpicelli, Frank M; Garcia, Luis I et al. (2009) Gap junction remodeling and spironolactone-dependent reverse remodeling in the hypertrophied heart. Circ Res 104:365-71|
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