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David L Paul - One of the best experts on this subject based on the ideXlab platform.
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the extracellular matrix controls Gap Junction Protein expression and function in postnatal hippocampal neural progenitor cells
BMC Neuroscience, 2009Co-Authors: Sophie Imbeault, Lianne Gauvin, Hadi Toeg, Alexandra Pettit, Catherine D Sorbara, Lamiaa Migahed, Rebecca Desroches, Sheila A Menzies, Kiyomasa Nishii, David L PaulAbstract:Background Gap Junction Protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells.
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the extracellular matrix controls Gap Junction Protein expression and function in postnatal hippocampal neural progenitor cells
BMC Neuroscience, 2009Co-Authors: Sophie Imbeault, Lianne Gauvin, Hadi Toeg, Alexandra Pettit, Catherine D Sorbara, Lamiaa Migahed, Rebecca Desroches, Sheila A Menzies, Kiyomasa Nishii, David L PaulAbstract:Gap Junction Protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells. We found that Cx26, Cx29, Cx30, Cx37, Cx40, Cx43, Cx45, and Cx47 mRNA and Protein but only Cx32 and Cx36 mRNA are detected in distinct neural progenitor cell populations cultured in the absence of exogenous ECM. Multipotential Type 1 cells express Cx26, Cx30, and Cx43 Protein. Their Type 2a progeny but not Type 2b and 3 neuronally committed progenitor cells additionally express Cx37, Cx40, and Cx45. Cx29 and Cx47 Protein is detected in early oligodendrocyte progenitors and mature oligodendrocytes respectively. Engagement with a laminin substrate markedly increases Cx26 Protein expression, decreases Cx40, Cx43, Cx45, and Cx47 Protein expression, and alters subcellular localization of Cx30. These changes are associated with decreased neurogenesis. Further, laminin elicits the appearance of Cx32 Protein in early oligodendrocyte progenitors and Cx36 Protein in immature neurons. These changes impact upon functional connexin-mediated hemichannel activity but not Gap Junctional intercellular communication. Together, these findings demonstrate a new role for extracellular matrix-cell interaction, specifically laminin, in the regulation of intrinsic connexin expression and function in postnatal neural progenitor cells.
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connexin32 is a myelin related Protein in the pns and cns
The Journal of Neuroscience, 1995Co-Authors: Steven S Scherer, Kenneth H Fischbeck, Suzanne M Deschenes, Judith B Grinspan, David L PaulAbstract:We have examined the expression of a Gap Junction Protein, connexin32 (Cx32), in Schwann cells and oligodendrocytes. In peripheral nerve, Cx32 is found in the paranodal myelin loops and Schmidt-Lanterman incisures of myelinating Schwann cells, and the levels of Cx32 Protein and mRNA change in parallel with those of other myelin-related genes during development, Wallerian degeneration, and axonal regeneration. In the central nervous system, Cx32 is found in oligodendrocytes and their processes, but not in compact myelin, and the levels of Cx32 Protein and mRNA increase during development in parallel with those of the other myelin genes. Thus, Cx32 is expressed as part of the myelinating phenotype of both Schwann cells and oligodendrocytes, indicating that this Gap Junction Protein plays in important role in the biology of myelin-forming cells.
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connexin mutations in x linked charcot marie tooth disease
Science, 1993Co-Authors: Joann Bergoffen, David L Paul, Steven S Scherer, Sumei Wang, M O Scott, L J Bone, K Chen, M W Lensch, P F Chance, Kenneth H FischbeckAbstract:X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the Gap Junction Protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a Gap Junction Protein, suggest that connexin32 plays an important role in peripheral nerve.
Sophie Imbeault - One of the best experts on this subject based on the ideXlab platform.
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the extracellular matrix controls Gap Junction Protein expression and function in postnatal hippocampal neural progenitor cells
BMC Neuroscience, 2009Co-Authors: Sophie Imbeault, Lianne Gauvin, Hadi Toeg, Alexandra Pettit, Catherine D Sorbara, Lamiaa Migahed, Rebecca Desroches, Sheila A Menzies, Kiyomasa Nishii, David L PaulAbstract:Background Gap Junction Protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells.
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the extracellular matrix controls Gap Junction Protein expression and function in postnatal hippocampal neural progenitor cells
BMC Neuroscience, 2009Co-Authors: Sophie Imbeault, Lianne Gauvin, Hadi Toeg, Alexandra Pettit, Catherine D Sorbara, Lamiaa Migahed, Rebecca Desroches, Sheila A Menzies, Kiyomasa Nishii, David L PaulAbstract:Gap Junction Protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells. We found that Cx26, Cx29, Cx30, Cx37, Cx40, Cx43, Cx45, and Cx47 mRNA and Protein but only Cx32 and Cx36 mRNA are detected in distinct neural progenitor cell populations cultured in the absence of exogenous ECM. Multipotential Type 1 cells express Cx26, Cx30, and Cx43 Protein. Their Type 2a progeny but not Type 2b and 3 neuronally committed progenitor cells additionally express Cx37, Cx40, and Cx45. Cx29 and Cx47 Protein is detected in early oligodendrocyte progenitors and mature oligodendrocytes respectively. Engagement with a laminin substrate markedly increases Cx26 Protein expression, decreases Cx40, Cx43, Cx45, and Cx47 Protein expression, and alters subcellular localization of Cx30. These changes are associated with decreased neurogenesis. Further, laminin elicits the appearance of Cx32 Protein in early oligodendrocyte progenitors and Cx36 Protein in immature neurons. These changes impact upon functional connexin-mediated hemichannel activity but not Gap Junctional intercellular communication. Together, these findings demonstrate a new role for extracellular matrix-cell interaction, specifically laminin, in the regulation of intrinsic connexin expression and function in postnatal neural progenitor cells.
Kiyomasa Nishii - One of the best experts on this subject based on the ideXlab platform.
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the extracellular matrix controls Gap Junction Protein expression and function in postnatal hippocampal neural progenitor cells
BMC Neuroscience, 2009Co-Authors: Sophie Imbeault, Lianne Gauvin, Hadi Toeg, Alexandra Pettit, Catherine D Sorbara, Lamiaa Migahed, Rebecca Desroches, Sheila A Menzies, Kiyomasa Nishii, David L PaulAbstract:Background Gap Junction Protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells.
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the extracellular matrix controls Gap Junction Protein expression and function in postnatal hippocampal neural progenitor cells
BMC Neuroscience, 2009Co-Authors: Sophie Imbeault, Lianne Gauvin, Hadi Toeg, Alexandra Pettit, Catherine D Sorbara, Lamiaa Migahed, Rebecca Desroches, Sheila A Menzies, Kiyomasa Nishii, David L PaulAbstract:Gap Junction Protein and extracellular matrix signalling systems act in concert to influence developmental specification of neural stem and progenitor cells. It is not known how these two signalling systems interact. Here, we examined the role of ECM components in regulating connexin expression and function in postnatal hippocampal progenitor cells. We found that Cx26, Cx29, Cx30, Cx37, Cx40, Cx43, Cx45, and Cx47 mRNA and Protein but only Cx32 and Cx36 mRNA are detected in distinct neural progenitor cell populations cultured in the absence of exogenous ECM. Multipotential Type 1 cells express Cx26, Cx30, and Cx43 Protein. Their Type 2a progeny but not Type 2b and 3 neuronally committed progenitor cells additionally express Cx37, Cx40, and Cx45. Cx29 and Cx47 Protein is detected in early oligodendrocyte progenitors and mature oligodendrocytes respectively. Engagement with a laminin substrate markedly increases Cx26 Protein expression, decreases Cx40, Cx43, Cx45, and Cx47 Protein expression, and alters subcellular localization of Cx30. These changes are associated with decreased neurogenesis. Further, laminin elicits the appearance of Cx32 Protein in early oligodendrocyte progenitors and Cx36 Protein in immature neurons. These changes impact upon functional connexin-mediated hemichannel activity but not Gap Junctional intercellular communication. Together, these findings demonstrate a new role for extracellular matrix-cell interaction, specifically laminin, in the regulation of intrinsic connexin expression and function in postnatal neural progenitor cells.
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mice lacking connexin45 conditionally in cardiac myocytes display embryonic lethality similar to that of germline knockout mice without endocardial cushion defect
Cell Communication and Adhesion, 2003Co-Authors: Kiyomasa Nishii, Madoka Kumai, Katsuko Egashira, Takeshi Miwa, Kanako Hashizume, Yumi Miyano, Yosaburo ShibataAbstract:The Gap Junction Protein connexin45-deficient (Cx45-KO) mice die shortly after the hearts begin to beat. In addition to the heart defect, they also show defective vascular development which may be ...
David C. Spray - One of the best experts on this subject based on the ideXlab platform.
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calmodulin dependent Protein kinase increases conductance at Gap Junctions formed by the neuronal Gap Junction Protein connexin36
Brain Research, 2012Co-Authors: Cristiane Del Corsso, Rolf Dermietzel, Rodolfo Iglesias, Georg Zoidl, David C. SprayAbstract:Abstract The major neuronal Gap Junction Protein connexin36 (Cx36) exhibits the remarkable property of “run-up”, in which Junctional conductance typically increases by 10-fold or more within 5–10 min following cell break-in with patch pipettes. Such conductance “run-up” is a unique property of Cx36, as it has not been seen in cell pairs expressing other connexins. Because of the recent observation describing CaMKII binding and phosphorylation sites in Cx36 and evidence that calmodulin dependent Protein kinase II (CaMKII) may potentiate electrical coupling in neurons of teleosts, we have explored whether CaMKII activates mammalian Cx36. Consistent with this hypothesis, certain Cx36 mutants lacking the CaMKII binding and phosphorylation sites or wild type Cx36 treated with certain cognate peptides corresponding to binding or phosphorylation sites blocked or strongly attenuated run-up of Junctional conductance. Likewise, KN-93, an inhibitor of CaMKII, blocked run-up, as did a membrane permeable peptide corresponding to the CaMKII autoinhibitory domain. Furthermore, run-up was blocked by phosphatase delivered within the pipette and not affected by treatment with the phosphatase inhibitor okadaic acid. These results imply that phosphorylation by CaMKII strengthens Junctional currents of Cx36 channels, thereby conferring functional plasticity on electrical synapses formed of this Protein.
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structural changes in the carboxyl terminus of the Gap Junction Protein connexin43 indicates signaling between binding domains for c src and zonula occludens 1
Journal of Biological Chemistry, 2004Co-Authors: Paul L Sorgen, Wanda Coombs, Heather S Duffy, Prangya Sahoo, Mario Delmar, David C. SprayAbstract:Abstract Regulation of cell-cell communication by the Gap Junction Protein connexin43 can be modulated by a variety of connexin-associating Proteins. In particular, c-Src can disrupt the connexin43 (Cx43)-zonula occludens-1 (ZO-1) interaction, leading to down-regulation of Gap Junction intercellular communication. The binding sites for ZO-1 and c-Src correspond to widely separated Cx43 domains (∼100 residues apart); however, little is known about the structural modifications that may allow information to be transferred over this distance. Here, we have characterized the structure of the connexin43 carboxyl-terminal domain (Cx43CT) to assess its ability to interact with domains from ZO-1 and c-Src. NMR data indicate that the Cx43CT exists primarily as an elongated random coil, with two regions of α-helical structure. NMR titration experiments determined that the ZO-1 PDZ-2 domain affected the last 19 Cx43CT residues, a region larger than that reported to be required for Cx43CT-ZO-1 binding. The c-Src SH3 domain affected Cx43CT residues Lys-264–Lys-287, Ser-306–Glu-316, His-331–Phe-337, Leu-356–Val-359, and Ala-367–Ser-372. Only region Lys-264–Lys-287 contains the residues previously reported to act as an SH3 binding domain. The specificity of these interactions was verified by peptide competition experiments. Finally, we demonstrated that the SH3 domain could partially displace the Cx43CT-PDZ-2 complex. These studies represent the first structural characterization of a connexin domain when integrated in a multimolecular complex. Furthermore, we demonstrate that the structural characteristics of a disordered Cx43CT are advantageous for signaling between different binding partners that may be important in describing the mechanism of channel closure or internalization in response to pathophysiological stimuli.
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array analysis of gene expression in connexin 43 null astrocytes
Physiological Genomics, 2003Co-Authors: Dumitru A Iacobas, Marcia Urbanmaldonado, Sanda Iacobas, Eliana Scemes, David C. SprayAbstract:Connexin-43 (Cx43) is the most abundant Gap Junction Protein in brain, where it is found primarily between astrocytes. Although the morphology of astrocytes from Cx43-null (knockout, KO) mice is si...
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Functional Properties of Channels Formed by the Neuronal Gap Junction Protein Connexin36
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999Co-Authors: Midituru Srinivas, Rolf Dermietzel, Renato Rozental, Takashi Kojima, Mark F. Mehler, Daniele F. Condorelli, John A. Kessler, David C. SprayAbstract:The expression and functional properties of connexin36 (Cx36) were examined in two communication-deficient cell lines (N2A-neuroblastoma and PC-12 cells) transfected with Cx36 and in hippocampal neurons that express the connexin endogenously. Transfected cells expressed the expected 2.9 kb Cx36 transcript and Cx36 immunoreactivity, whereas nontransfected cells were devoid of Cx36. The relationship between steady-state Junctional conductance (g(j)) and transJunctional voltage was well described by a two-state Boltzmann equation. The half-inactivation voltage (V(0)), the ratio of minimal to maximal g(j) (g(min)/g(max)), and the equivalent gating charge were +/- 75 mV, 0.55, and 1.75, respectively, indicating that Cx36 exhibits very low voltage sensitivity. Conductance of single Cx36 channels measured with patch pipettes containing 130 mM CsCl was 10-15 pS (n = 15 cell pairs); despite this low unitary conductance, Cx36 channels were permeable to the dye Lucifer yellow. Hippocampal neurons expressed Cx36 both in vivo and in culture. The electrophysiological properties of channels in cultured hippocampal neurons were similar to those of the channels expressed by the transfected cell lines, and the neuronal channels were similarly permeable to Lucifer yellow. The unique combination of weak voltage sensitivity, small unitary conductance, and permeation by anions as large as second messenger molecules endows Cx36 Gap Junction channels with properties well suited for mediating flexible electrical and biochemical interactions between neurons.
Elissavet Kardami - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation of serine 262 in the Gap Junction Protein connexin-43 regulates DNA synthesis in cell-cell contact forming cardiomyocytes.
Journal of cell science, 2004Co-Authors: Bradley W Doble, Robert R Fandrich, Xitong Dang, Peipei Ping, Barbara E Nickel, Yan Jin, Peter A Cattini, Elissavet KardamiAbstract:Mitogenic stimulation of cardiomyocytes is associated with decreased Gap Junction coupling and Protein kinase C (PKC)-mediated phosphorylation of the Gap Junction Protein connexin43 (Cx43). Identification of and interference with the amino acid(s) that becomes phosphorylated in response to stimulation are important steps towards defining the relationship between Cx43 phosphorylation and cell cycle. Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (S262) on Cx43 becomes phosphorylated in response to growth factor or PKC stimulation of cardiomyocytes. To examine the effect of Cx43, S262 phosphorylation and cell-cell contact (and/or coupling) on DNA synthesis, we overexpressed wild-type (wt) or mutant Cx43, carrying a S262-to-alanine (S262A, simulating the unphosphorylated state) or a S262-to-aspartate (S262D, simulating constitutive phosphorylation) substitutions in cultures of cell-cell contact forming or isolated cardiomyocytes. Overexpression of wt-Cx43 caused a significant decrease in DNA synthesis irrespective of the presence of cell-cell contact. In cell-cell contact forming cultures, the S262D mutation reversed while the S262A mutation increased the inhibitory effect of Cx43. In the absence of cell-cell contact, the S262-Cx43 mutations had no significant effect on Cx43 inhibition of DNA synthesis. Dye-coupling, evaluated by scrape-loading, indicated increased Gap Junction permeability in S262A (compared to wt or S262D) overexpressing myocytes. We conclude that Cx43 inhibits cardiomyocyte DNA synthesis irrespectively of cell-cell contact or coupling. Cell-cell contact, and possibly Gap Junction-mediated communication is required, however, in order to reverse Cx43 inhibition of DNA synthesis by S262 phosphorylation.
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ischemia induced dephosphorylation of cardiomyocyte connexin 43 is reduced by okadaic acid and calyculin a but not fostriecin
Molecular and Cellular Biochemistry, 2003Co-Authors: Madhumathy Jeyaraman, Stephane Tanguy, Robert R Fandrich, Anton Lukas, Elissavet KardamiAbstract:The Gap Junction Protein connexin-43 (Cx43) exists mainly in the phosphorylated state in the normal heart, while ischemia induces dephosphorylation. Phosphatase(s) involved in cardiac Cx43 dephosphorylation have not as yet been identified. We examined the acute effects of ischemia on the dephosphorylation of the Gap Junction Protein connexin-43 in isolated adult cardiomyocytes and isolated perfused hearts. In addition we tested the effectiveness of Protein phosphatase 1 and 2A (PP1/2A) inhibitors in preventing Cx43 dephosphorylation. In both models, significant accumulation of the 41 kDa non-phosphorylated Cx43, accompanied by decreased relative levels of the 43–46 kDa phosphorylated Cx43, was observed at 30 min of ischemia. Okadaic acid decreased ischemia-induced Cx43 dephosphorylation; it also decreased the accumulation of non-phosphorylated Cx43 at the intercalated discs of myocytes in the whole heart. Calyculin A, but not fostriecin, also decreased ischemia-induced Cx43 dephosphorylation in isolated cardiomyocytes. It is concluded that isolated adult myocytes respond to ischemia in a manner similar to whole hearts and that ischemia-induced dephosphorylation of Cx43 is mediated, at least in part, by PP1-like phosphatase(s).
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Ischemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by okadaic acid and calyculin A but not fostriecin
Cardiac Cell Biology, 2003Co-Authors: Madhumathy Jeyaraman, Stephane Tanguy, Robert R Fandrich, Anton Lukas, Elissavet KardamiAbstract:The Gap Junction Protein connexin-43 (Cx43) exists mainly in the phosphorylated state in the normal heart, while ischemia induces dephosphorylation. Phosphatase(s) involved in cardiac Cx43 dephosphorylation have not as yet been identified. We examined the acute effects of ischemia on the dephosphorylation of the Gap Junction Protein connexin-43 in isolated adult cardiomyocytes and isolated perfused hearts. In addition we tested the effectiveness of Protein phosphatase 1 and 2A (PP1/2A) inhibitors in preventing Cx43 dephosphorylation. In both models, significant accumulation of the 41 kDa non-phosphorylated Cx43, accompanied by decreased relative levels of the 43–46 kDa phosphorylated Cx43, was observed at 30 min of ischemia. Okadaic acid decreased ischemia-induced Cx43 dephosphorylation; it also decreased the accumulation of non-phosphorylated Cx43 at the intercalated discs of myocytes in the whole heart. Calyculin A, but not fostriecin, also decreased ischemia-induced Cx43 dephosphorylation in isolated cardiomyocytes. It is concluded that isolated adult myocytes respond to ischemia in a manner similar to whole hearts and that ischemia-induced dephosphorylation of Cx43 is mediated, at least in part, by PP1like phosphatase(s). (Mol Cell Biochem 242: 129–134, 2003)
