The Experts below are selected from a list of 7272 Experts worldwide ranked by ideXlab platform
David L Paul - One of the best experts on this subject based on the ideXlab platform.
-
Connexins functions without junctions
Current Opinion in Cell Biology, 2004Co-Authors: Charles Stout, Daniel A. Goodenough, David L PaulAbstract:Emerging studies indicate that Connexins have activities completely unrelated to gap junctions and, conversely, that non-connexin proteins can form gap junction channels.
-
genetic diseases and gene knockouts reveal diverse connexin functions
Annual Review of Physiology, 1999Co-Authors: Thomas W. White, David L PaulAbstract:Intercellular channels present in gap junctions allow cells to share small molecules and thus coordinate a wide range of behaviors. Remarkably, although junctions provide similar functions in all multicellular organisms, vertebrates and invertebrates use unrelated gene families to encode these channels. The recent identification of the invertebrate innexin family opens up powerful genetic systems to studies of intercellular communication. At the same time, new information on the physiological roles of vertebrate Connexins has emerged from genetic studies. Mutations in connexin genes underlie a variety of human diseases, including deafness, demyelinating neuropathies, and lens cataracts. In addition, gene targeting of Connexins in mice has provided new insights into connexin function and the significance of connexin diversity.
-
connections with Connexins the molecular basis of direct intercellular signaling
FEBS Journal, 1996Co-Authors: Roberto Bruzzone, Thomas W. White, David L PaulAbstract:Adjacent cells share ions, second messengers and small metabolites through intercellular channels which are present in gap junctions. This type of intercellular communication permits coordinated cellular activity, a critical feature for organ homeostasis during development and adult life of multicellular organisms. Intercellular channels are structurally more complex than other ion channels, because a complete cell-to-cell channel spans two plasma membranes and results from the association of two half channels, or connexons, contributed separately by each of the two participating cells. Each connexon, in turn, is a multimenc assembly of protein subunits. The structural proteins comprising these channels, collectively called Connexins, are members of a highly related multigene family consisting of at least 13 members. Since the cloning of the first connexin in 1986, considerable progress has been made in our understanding of the complex molecular switches that control the formation and permeability of intercellular channels. Analysis of the mechanisms of channel assembly has revealed the selectivity of inter-connexin interactions and uncovered novel characteristics of the channel permeability and gating behavior. Structure/function studies have begun to provide a molecular understanding of the significance of connexin diversity and demonstrated the unique regulation of Connexins by tyrosine kinases and oncogenes. Finally, mutations in two connexin genes have been linked to human diseases. The development of more specific approaches (dominant negative mutants, knockouts, transgenes) to study the functional role of Connexins in organ homeostasis is providing a new perception about the significance of connexin diversity and the regulation of intercellular communication.
-
Connexins, CONNEXONS, AND INTERCELLULAR COMMUNICATION
Annual review of biochemistry, 1996Co-Authors: Daniel A. Goodenough, Jeffrey A. Goliger, David L PaulAbstract:Cells in tissues share ions, second messengers, and small metabolites through clusters of intercellular channels called gap junctions. This type of intercellular communication permits coordinated cellular activity. Intercellular channels are formed from two oligomeric integral membrane protein assemblies, called connexons, which span two adjacent cells' plasma membranes and join in a narrow, extracellular "gap." Connexons are formed from Connexins, a highly related multigene family consisting of at least 13 members. Since the cloning of the first connexin in 1986, considerable progress has been made in our understanding of the complex molecular switches that control the formation and permeability of the intercellular channels. Analysis of the mechanisms of channel assembly has revealed the selectivity of inter-connexin interactions and uncovered novel characteristics of the channel permeability and gating behavior. Structure-function studies provide a molecular understanding of the significance of connexin diversity and demonstrate the unique regulation of Connexins by tyrosine kinases and oncogenes.
-
functional analysis of selective interactions among rodent Connexins
Molecular Biology of the Cell, 1995Co-Authors: Thomas W. White, Daniel A. Goodenough, David L Paul, Roberto BruzzoneAbstract:One consequence of the diversity in gap junction structural proteins is that cells expressing different Connexins may come into contact and form intercellular channels that are mixed in connexin content. We have systematically examined the ability of adjacent cells expressing different Connexins to communicate, and found that all Connexins exhibit specificity in their interactions. Two extreme examples of selectivity were observed. Connexin40 (Cx40) was highly restricted in its ability to make heterotypic channels, functionally interacting with Cx37, but failing to do so when paired with Cx26, Cx32, Cx43, Cx46, and Cx50. In contrast, Cx46 interacted well with all Connexins tested except Cx40. To explore the molecular basis of connexin compatibility and voltage gating, we utilized a chimera consisting of Cx32 from the N-terminus to the second transmembrane domain, fused to Cx43 from the middle cytoplasmic loop to the C-terminus. The chimeric connexin behaved like Cx43 with regard to selectivity and like Cx32 with regard to voltage dependence. Taken together, these results demonstrate that the second but not the first extracellular domain affects compatibility, whereas voltage gating is strongly influenced by sequences between the N-terminus and the second transmembrane domain.
Luc Leybaert - One of the best experts on this subject based on the ideXlab platform.
-
connexin 43 is an emerging therapeutic target in ischemia reperfusion injury cardioprotection and neuroprotection
Pharmacology & Therapeutics, 2015Co-Authors: Rainer Schulz, Philipp Maximilian Gorge, Aniko Gorbe, Peter Ferdinandy, Paul D Lampe, Luc LeybaertAbstract:Connexins are widely distributed proteins in the body that are crucially important for heart and brain functions. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localization at the sarcolemma of cardiomyocytes and brain cells, Connexins are also found in the mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodeling or heart failure, and post-translationally Connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the Connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injuries as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissues following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection.
Dale W Laird - One of the best experts on this subject based on the ideXlab platform.
-
Connexins and Disease
Cold Spring Harbor perspectives in biology, 2018Co-Authors: Mario Delmar, Morten Schak Nielsen, Dale W Laird, Christian C. Naus, Vytautas Verselis, Thomas W. WhiteAbstract:Inherited or acquired alterations in the structure and function of connexin proteins have long been associated with disease. In the present work, we review current knowledge on the role of Connexins in diseases associated with the heart, nervous system, cochlea, and skin, as well as cancer and pleiotropic syndromes such as oculodentodigital dysplasia (ODDD). Although incomplete by virtue of space and the extent of the topic, this review emphasizes the fact that connexin function is not only associated with gap junction channel formation. As such, both canonical and noncanonical functions of Connexins are fundamental components in the pathophysiology of multiple connexin related disorders, many of them highly debilitating and life threatening. Improved understanding of connexin biology has the potential to advance our understanding of mechanisms, diagnosis, and treatment of disease.
-
SnapShot: Connexins and Disease.
Cell, 2017Co-Authors: Dale W Laird, Christian C. Naus, Paul D LampeAbstract:The connexin family of membrane proteins enable gap junction formation and homeostasis, supporting communication between adjacent cells. This SnapShot highlights mutations in different Connexins associated with human pathologies and how they affect gap junction function.
-
Connexins and Gap Junctions in Mammary Gland Development and Breast Cancer Progression
Journal of Membrane Biology, 2007Co-Authors: Elizabeth Mclachlan, Qing Shao, Dale W LairdAbstract:The development and function of the mammary gland require precise control of gap junctional intercellular communication (GJIC). Here, we review the expression and function of gap junction proteins, Connexins, in the normal mouse and human mammary gland. We then discuss the possible tumor-suppressive role of Cx26 and Cx43 in primary breast tumors and through the various stages of breast cancer metastasis and consider whether Connexins or GJIC may actually promote tumorigenesis at some stages. Finally, we present in vitro data on the impact of connexin expression on breast cancer cell metastasis to the bone. We observed that Cx43 expression inhibited the invasive and migratory potentials of MDA-MB-231 breast cancer cells in a bone microenvironment, provided by the MC3T3-E1 mouse osteoblastic cell line. Expression of either Cx26 or Cx43 had no effect on MDA-MB-231 growth and adhesion under the influence of osteoblasts and did not result in regulation of osteogenic gene expression in these breast cancer cells. Furthermore, connexin-expressing MDA-MB-231 cells did not have an effect on the growth or differentiation of MC3T3-E1 cells. In summary, we conclude that connexin expression and GJIC are integral to the development and differentiation of the mammary gland. In breast cancer, Connexins generally act as tumor suppressors in the primary tumor; however, in advanced breast tumors, Connexins appear to act as both context-dependent tumor suppressors and facilitators of disease progression.
-
Connexins act as tumor suppressors in three dimensional mammary cell organoids by regulating differentiation and angiogenesis
Cancer Research, 2006Co-Authors: Elizabeth Mclachlan, Qing Shao, Hongling Wang, Stephanie Langlois, Dale W LairdAbstract:Connexins are tumor suppressors, and human breast connexin 26 (Cx26) and connexin 43 (Cx43) gap junctions are often down-regulated in breast cancer. We previously showed that Cx26 and Cx43 overexpressed in MDA-MB-231 breast cancer cells inhibited tumor growth in vivo but not in two-dimensional cultures. In the current study, we show that overexpression of Cx26 or Cx43 has tumor-suppressive properties in a three-dimensional environment such that they reduced anchorage-independent cell growth and induced partial redifferentiation of three-dimensional organoids of MDA-MB-231 cells. Importantly, the majority of exogenous Connexins did not localize to the cell-cell interface or rescue gap junctional intercellular communication (GJIC) as assessed by dye transfer, providing evidence of a GJIC-independent mechanism of mammary tumor suppression. To further elucidate the mechanisms involved in connexin-induced three-dimensional redifferentiation of tumor cells, we examined whether connexin expression has a role in epithelial to mesenchymal transition (EMT). Cx26 and Cx43 reduced cell migration, increased cytokeratin 18 expression, and decreased vimentin levels, indicating a shift from a mesenchymal towards an epithelial phenotype. In addition, we examined the role of Connexins in angiogenesis by probing an angiogenesis antibody array with conditioned media from three-dimensional MDA-MB-231 cultures. This revealed that connexin overexpression regulated various angiogenesis-linked proteins. Furthermore, secreted factors from connexin overexpressing cells inhibited endothelial cell tubulogenesis and migration, and xenografts of Cx43 overexpressing MDA-MB-231 cells showed reduced tumor angiogenesis. In summary, Cx26 and Cx43 inhibit the malignant properties of MDA-MB-231 cells via GJIC-independent mechanisms, including regulation of EMT and angiogenesis.
-
connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation
Biochimica et Biophysica Acta, 2005Co-Authors: Dale W LairdAbstract:Gap junction proteins, Connexins, are dynamic polytopic membrane proteins that exhibit unprecedented short half-lives of only a few hours. Consequently, it is well accepted that in addition to channel gating, gap junctional intercellular communication is regulated by connexin biosynthesis, transport and assembly as well as the formation and removal of gap junctions from the cell surface. At least nine members of the 20-member connexin family are known to be phosphorylated en route or during their assembly into gap junctions. For some Connexins, notably Cx43, evidence exists that phosphorylation may trigger its internalization and degradation. In recent years it has become apparent that the mechanisms underlying the regulation of connexin turnover are quite complex with the identification of many connexin binding molecules, a multiplicity of protein kinases that phosphorylate Connexins and the involvement of both lysosomal and proteasomal pathways in degrading Connexins. This paper will review the evidence that connexin phosphorylation regulates, stimulates or triggers gap junction disassembly, internalization and degradation.
Paul D Lampe - One of the best experts on this subject based on the ideXlab platform.
-
SnapShot: Connexins and Disease.
Cell, 2017Co-Authors: Dale W Laird, Christian C. Naus, Paul D LampeAbstract:The connexin family of membrane proteins enable gap junction formation and homeostasis, supporting communication between adjacent cells. This SnapShot highlights mutations in different Connexins associated with human pathologies and how they affect gap junction function.
-
connexin 43 is an emerging therapeutic target in ischemia reperfusion injury cardioprotection and neuroprotection
Pharmacology & Therapeutics, 2015Co-Authors: Rainer Schulz, Philipp Maximilian Gorge, Aniko Gorbe, Peter Ferdinandy, Paul D Lampe, Luc LeybaertAbstract:Connexins are widely distributed proteins in the body that are crucially important for heart and brain functions. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localization at the sarcolemma of cardiomyocytes and brain cells, Connexins are also found in the mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodeling or heart failure, and post-translationally Connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the Connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injuries as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissues following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection.
-
regulation of gap junctions by phosphorylation of Connexins
Archives of Biochemistry and Biophysics, 2000Co-Authors: Paul D Lampe, Alan F. LauAbstract:Gap junctions are a unique type of intercellular junction found in most animal cell types. Gap junctions permit the intercellular passage of small molecules and have been implicated in diverse biological processes, such as development, cellular metabolism, and cellular growth control. In vertebrates, gap junctions are composed of proteins from the "connexin" gene family. The majority of Connexins are modified posttranslationally by phosphorylation, primarily on serine amino acids; however, phosphotyrosine has also been detected in connexin from cells coexpressing nonreceptor tyrosine protein kinases. Connexins are targeted by numerous protein kinases, of which some have been identified: protein kinase C, mitogen-activated protein kinase, and the v-Src tyrosine protein kinase. Phosphorylation has been implicated in the regulation of a broad variety of connexin processes, such as the trafficking, assembly/disassembly, degradation, as well as the gating of gap junction channels. This review examines the consequences of connexin phosphorylation for the regulation of gap junctional communication.
Thomas W. White - One of the best experts on this subject based on the ideXlab platform.
-
Connexins and Disease
Cold Spring Harbor perspectives in biology, 2018Co-Authors: Mario Delmar, Morten Schak Nielsen, Dale W Laird, Christian C. Naus, Vytautas Verselis, Thomas W. WhiteAbstract:Inherited or acquired alterations in the structure and function of connexin proteins have long been associated with disease. In the present work, we review current knowledge on the role of Connexins in diseases associated with the heart, nervous system, cochlea, and skin, as well as cancer and pleiotropic syndromes such as oculodentodigital dysplasia (ODDD). Although incomplete by virtue of space and the extent of the topic, this review emphasizes the fact that connexin function is not only associated with gap junction channel formation. As such, both canonical and noncanonical functions of Connexins are fundamental components in the pathophysiology of multiple connexin related disorders, many of them highly debilitating and life threatening. Improved understanding of connexin biology has the potential to advance our understanding of mechanisms, diagnosis, and treatment of disease.
-
gap junctions basic structure and function
Journal of Investigative Dermatology, 2007Co-Authors: Gulistan Mese, Gabriele Richard, Thomas W. WhiteAbstract:Gap junctions allow the exchange of ions, second messengers, and small metabolites between adjacent cells and are formed by two unrelated protein families, the pannexins and Connexins. Mutations in connexin genes cause a variety of genetic disorders, implicating a critical role in tissue homeostasis. Association of congenital skin disorders to mutations in different Connexins has underscored the importance of gap junctional communication in the skin and its appendages. Here, we discuss the basic structure of gap junction channels and the function of connexin genes that have been associated with human disorders to explore the physiology of intercellular communication in skin.
-
cloning and functional expression of invertebrate Connexins from halocynthia pyriformis
FEBS Letters, 2004Co-Authors: Thomas W. White, Jennifer Litteral, Huan Wang, Peter R BrinkAbstract:Unlike many other ion channels, unrelated gene families encode gap junctions in different animal phyla. Connexin and pannexin genes are found in deuterostomes, while protostomal species use innexin genes. Connexins are often described as vertebrate genes, despite the existence of invertebrate deuterostomes. We have cloned connexin sequences from an invertebrate chordate, Halocynthia pyriformis. Invertebrate Connexins shared 25–40% sequence identity with human Connexins, had extracellular domains containing six invariant cysteine residues, coding regions that were interrupted by introns, and formed functional channels in vitro. These data show that gap junction channels based on Connexins are present in animals that predate vertebrate evolution.
-
genetic diseases and gene knockouts reveal diverse connexin functions
Annual Review of Physiology, 1999Co-Authors: Thomas W. White, David L PaulAbstract:Intercellular channels present in gap junctions allow cells to share small molecules and thus coordinate a wide range of behaviors. Remarkably, although junctions provide similar functions in all multicellular organisms, vertebrates and invertebrates use unrelated gene families to encode these channels. The recent identification of the invertebrate innexin family opens up powerful genetic systems to studies of intercellular communication. At the same time, new information on the physiological roles of vertebrate Connexins has emerged from genetic studies. Mutations in connexin genes underlie a variety of human diseases, including deafness, demyelinating neuropathies, and lens cataracts. In addition, gene targeting of Connexins in mice has provided new insights into connexin function and the significance of connexin diversity.
-
connections with Connexins the molecular basis of direct intercellular signaling
FEBS Journal, 1996Co-Authors: Roberto Bruzzone, Thomas W. White, David L PaulAbstract:Adjacent cells share ions, second messengers and small metabolites through intercellular channels which are present in gap junctions. This type of intercellular communication permits coordinated cellular activity, a critical feature for organ homeostasis during development and adult life of multicellular organisms. Intercellular channels are structurally more complex than other ion channels, because a complete cell-to-cell channel spans two plasma membranes and results from the association of two half channels, or connexons, contributed separately by each of the two participating cells. Each connexon, in turn, is a multimenc assembly of protein subunits. The structural proteins comprising these channels, collectively called Connexins, are members of a highly related multigene family consisting of at least 13 members. Since the cloning of the first connexin in 1986, considerable progress has been made in our understanding of the complex molecular switches that control the formation and permeability of intercellular channels. Analysis of the mechanisms of channel assembly has revealed the selectivity of inter-connexin interactions and uncovered novel characteristics of the channel permeability and gating behavior. Structure/function studies have begun to provide a molecular understanding of the significance of connexin diversity and demonstrated the unique regulation of Connexins by tyrosine kinases and oncogenes. Finally, mutations in two connexin genes have been linked to human diseases. The development of more specific approaches (dominant negative mutants, knockouts, transgenes) to study the functional role of Connexins in organ homeostasis is providing a new perception about the significance of connexin diversity and the regulation of intercellular communication.