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.
|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|
|Aasen, Trond; Mesnil, Marc; Naus, Christian C et al. (2016) Gap junctions and cancer: communicating for 50 years. Nat Rev Cancer 16:775-788|
|Morel, Sandrine; Christoffersen, Christina; Axelsen, Lene N et al. (2016) Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. Cardiovasc Res 109:385-96|
|Solan, Joell L; Lampe, Paul D (2016) Kinase programs spatiotemporally regulate gap junction assembly and disassembly: Effects on wound repair. Semin Cell Dev Biol 50:40-8|
|Puebla, Carlos; Cisterna, Bruno A; Salas, Daniela P et al. (2016) Linoleic acid permeabilizes gastric epithelial cells by increasing connexin 43 levels in the cell membrane via a GPR40- and Akt-dependent mechanism. Biochim Biophys Acta 1861:439-48|
|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|
|Riquelme, Manuel A; Burra, Sirisha; Kar, Rekha et al. (2015) Mitogen-activated Protein Kinase (MAPK) Activated by Prostaglandin E2 Phosphorylates Connexin 43 and Closes Osteocytic Hemichannels in Response to Continuous Flow Shear Stress. J Biol Chem 290:28321-8|
|Meraviglia, Viviana; Azzimato, Valerio; Colussi, Claudia et al. (2015) Acetylation mediates Cx43 reduction caused by electrical stimulation. J Mol Cell Cardiol 87:54-64|
|Salas, Daniela; Puebla, Carlos; Lampe, Paul D et al. (2015) Role of Akt and Ca2+ on cell permeabilization via connexin43 hemichannels induced by metabolic inhibition. Biochim Biophys Acta 1852:1268-77|
|Schulz, Rainer; GÃ¶rge, Philipp Maximilian; GÃ¶rbe, AnikÃ³ et al. (2015) Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther 153:90-106|
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