Long range intercellular communication among astrocytes is in large part mediated by gap junction channels, through which ions and metabolites pass directly from one cell to the next. The pore of astrocyte gap junctions is formed primarily of the gap junction protein connexin43 (Cx43). Recent evidence indicates that other proteins are associated with Cx43 at gap junctions, forming a macromolecular complex that we have termed the Nexus. We hypothesize that the Nexus components may regulate both the properties of the gap junction channels and also may function in intracellular signal transduction and trafficking of Cx43 within the astrocyte, all of which are critical for maintaining the network of coupled astrocytes throughout the brain. During the last period of support, we found that both intra- and intermolecular interactions occur with Cx43, have quantified the affinities of several interactions under different pH and phosphorylation conditions and used NMR to solve structures of relevant Cx43 cytoplasmic domains and to determine how structures change upon binding. We have also identified new binding partners for Cx43 and have begun to examine how interaction with binding partners affects function of Cx43 gap junction channels and the intracellular trafficking of this protein to and from the membrane. The Nexus complex in astrocytes is thus dynamic, changing binding partner affinities due to local conditions and local concentrations of ligands. We now propose to extend these studies to determine how interactions of cytoskeletal proteins with Cx43 is linked to both rapid and gradual remodeling of the astrocyte network. The proposed studies use an interdisciplinary approach with several techniques that are new to the gap junction field to rigorously explore the novel concept that connexin-cytoskeletal interaction is a major determinant of gap junction function in astrocytes. As such, these studies are expected to lead to novel insight of roles that gap junctions play in the nervous system and elsewhere.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
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Bosetti, Francesca
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Albert Einstein College of Medicine
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Friedman, L K; Mancuso, J; Patel, A et al. (2013) Transcriptome profiling of hippocampal CA1 after early-life seizure-induced preconditioning may elucidate new genetic therapies for epilepsy. Eur J Neurosci 38:2139-52
Spray, David C; Hanstein, Regina; Lopez-Quintero, Sandra V et al. (2013) Gap junctions and Bystander Effects: Good Samaritans and executioners. Wiley Interdiscip Rev Membr Transp Signal 2:1-15
Hanstein, Regina; Negoro, Hiromitsu; Patel, Naman K et al. (2013) Promises and pitfalls of a Pannexin1 transgenic mouse line. Front Pharmacol 4:61
Iacobas, S; Iacobas, D A; Spray, D C et al. (2012) The connexin43-dependent transcriptome during brain development: importance of genetic background. Brain Res 1487:131-9
Del Corsso, Cristiane; Iglesias, Rodolfo; Zoidl, Georg et al. (2012) Calmodulin dependent protein kinase increases conductance at gap junctions formed by the neuronal gap junction protein connexin36. Brain Res 1487:69-77
Suadicani, Sylvia O; Iglesias, Rodolfo; Wang, Junjie et al. (2012) ATP signaling is deficient in cultured Pannexin1-null mouse astrocytes. Glia 60:1106-16
Santiago, Marcelo F; Alcami, Pepe; Striedinger, Katharine M et al. (2010) The carboxyl-terminal domain of connexin43 is a negative modulator of neuronal differentiation. J Biol Chem 285:11836-45
Thi, Mia M; Urban-Maldonado, Marcia; Spray, David C et al. (2010) Characterization of hTERT-immortalized osteoblast cell lines generated from wild-type and connexin43-null mouse calvaria. Am J Physiol Cell Physiol 299:C994-C1006
Desruisseaux, Mahalia S; Iacobas, Dumitru A; Iacobas, Sanda et al. (2010) Alterations in the Brain Transcriptome in Plasmodium Berghei ANKA Infected Mice. J Neuroparasitology 1:
Thi, Mia M; Suadicani, Sylvia O; Spray, David C (2010) Fluid flow-induced soluble vascular endothelial growth factor isoforms regulate actin adaptation in osteoblasts. J Biol Chem 285:30931-41

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