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BBA - Biomembranes (v.1711, #2)
Structural organization of gap junction channels by Gina E. Sosinsky; Bruce J. Nicholson (pp. 99-125).
Gap junctions were initially described morphologically, and identified as semi-crystalline arrays of channels linking two cells. This suggested that they may represent an amenable target for electron and X-ray crystallographic studies in much the same way that bacteriorhodopsin has. Over 30 years later, however, an atomic resolution structural solution of these unique intercellular pores is still lacking due to many challenges faced in obtaining high expression levels and purification of these structures. A variety of microscopic techniques, as well as NMR structure determination of fragments of the protein, have now provided clearer and correlated views of how these structures are assembled and function as intercellular conduits. As a complement to these structural approaches, a variety of mutagenic studies linking structure and function have now allowed molecular details to be superimposed on these lower resolution structures, so that a clearer image of pore architecture and its modes of regulation are beginning to emerge.
Keywords: Gap junction; Connexin; Structure; Mutagenesis; Electron microscopy; NMR; Atomic force microscopy; Pore structure; Gating
Functional consequences of heterogeneous gap junction channel formation and its influence in health and disease by G. Trevor Cottrell; Janis M. Burt (pp. 126-141).
The capacity of multiple connexins to hetero-oligomerize into functional heterogeneous gap junction channels has been demonstrated in vivo11Used herein to denote in an animal., in vitro22Used herein to denote in cultured cells., and in nonmammalian expression systems. These heterogeneous channels display gating activity, channel conductances, selectivity and regulatory behaviors that are sometimes not predicted by the behaviors of the corresponding homogeneous channels. Such observations suggest that heteromerization of gap junction proteins offers an efficient cellular strategy for finely regulating cell-to-cell communication. The available evidence strongly indicates that heterogeneous gap junction assembly is important to normal growth and differentiation, and may influence the appearance of several disease states. Definitive evidence that heterogeneous gap junction channels differentially regulate electrical conduction in excitable cells is absent. This review examines the prevalence, regulation, and implications of gap junction channel hetero-oligomerization.
Keywords: Gap junction; Connexin; Connexon; Heteromeric; Heterotypic; Junctional conductance; Unitary conductance; Selective permeability
Connexins and their environment: effects of lipids composition on ion channels by Michael Cascio (pp. 142-153).
Intercellular communication is mediated through paired connexons that form an aqueous pore between two adjacent cells. These membrane proteins reside in the plasma membrane of their respective cells and their activity is modulated by the composition of the lipid bilayer. The effects of the bilayer on connexon structure and function may be direct or indirect, and may arise from specific binding events or the physicochemical properties of the bilayer. While the effects of the bilayer and its constituent lipids on gap junction activity have been described in the literature, the underlying mechanisms of the interaction of connexin with its lipidic microenvironment are not as well characterized. Given that the information regarding connexons is limited, in this review, the specific roles of lipids and the properties of the bilayer on membrane protein structure and function are described for other ion channels as well as for connexons.
Keywords: Connexin; Gap junction; Ion channel; Membrane lipid; Lipid–protein interaction; Cholesterol; Fatty acid; Lipid raft; Caveolin
Connexin phosphorylation as a regulatory event linked to gap junction channel assembly by Joell L. Solan; Paul D. Lampe (pp. 154-163).
Gap junctions, composed of proteins from the connexin family, allow for intercellular communication between cells and are important in development and maintenance of cell homeostasis. Phosphorylation has been implicated in the regulation of gap junctional communication at several stages of the cell cycle and the connexin “lifecycle�, such as trafficking, assembly/disassembly, degradation, as well as in the gating of “hemi� channels or intact gap junction channels. This review focuses on how phosphorylation can regulate the early stages of the connexin life cycle through assembly of functional gap junctional channels. The availability of sequences from the human genome databases has indicated that the number of connexins in the gene family is approximately 20, but we know mostly about how connexin43 (Cx43) is regulated. Recent technologies and investigations of interacting proteins have shown that activation of several kinases including protein kinase A, protein kinase C (PKC), p34cdc2/cyclin B kinase, casein kinase 1 (CK1), mitogen-activated protein kinase (MAPK) and pp60src kinase can lead to phosphorylation of the majority of the 21 serine and two of the tyrosine residues in the C-terminal region of Cx43. While many studies have correlated changes in kinase activity with changes in gap junctional communication, further research is needed to directly link specific phosphorylation events with changes in connexin oligomerization and gap junction assembly.
Keywords: Abbreviations; Cx; connexin; PKA; cAMP-dependent protein kinase; MAPK; mitogen-activated protein kinase; PKC; protein kinase C; CK1; casein kinase 1; PMA; phorbol 12-myristate 13-acetate; FSH; follicle stimulating hormone; NP; non-phosphorylated; SDS-PAGE; sodium dodecylsulfate-polyacrylamide gel electrophoresisConnexin; Gap junction; Phosphorylation; Cell signaling; PKC; PKA; Casein kinase
Connexin phosphorylation as a regulatory event linked to channel gating by Alonso P. Moreno (pp. 164-171).
The main proteins required for functional gap junction channels are known as connexins and most of their isoforms indicate that they can become phosphorylated. Connexin phosphorylation has been reported to participate in modifying junctional communication and the mechanisms involved apparently depend on which kinase becomes involved. Although multiple reports have suggested a strong influence of phosphorylation on channel gating, not enough physiological studies have been performed to determine precisely the gating mechanisms implicated. Moreover, gap junction channels follow other various gating mechanisms, including voltage gating and chemical gating, where phosphorylation could act as a modulator. The quest for this chapter has been to discriminate those instances where phosphorylation acts directly as a gating trigger and where it acts indirectly or only as a modulator. Despite recent efforts, the mechanisms involved in all these cases are barely understood.
Keywords: Gap junction; Gating; Protein phosphorylation; Cell to cell coupling
Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation by Dale W. Laird (pp. 172-182).
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.
Keywords: Connexin; Gap junction; Internalization; Degradation; Phosphorylation
Sensitivity of the brain transcriptome to connexin ablation by Dumitru A. Iacobas; Sanda Iacobas; Marcia Urban-Maldonado; David C. Spray (pp. 183-196).
Extensive studies on mice with total or partial disruption of either connexin43 (Cx43) or connexin32 (Cx32) have detected only subtle changes in central nervous system structure, growth, development, or function. We have used high density cDNA arrays to analyze the regulation, control, and coordination of the abundances of 7446 distinct transcripts in four brains, each of Cx43 null (K43), Cx43 heterozygous (H43), and Cx32 null (K32) mice as compared to the brains of wildtype (W) mice. The use of multiple samples allowed the determination of the statistical significance of gene regulation. Significantly regulated genes encoded proteins of all functional categories, extending beyond those that might be expected to depend on junctional communication. Moreover, we found a high degree of similarity between genes regulated in the K43 and H43 brains and a remarkable overlap between gene regulation in brains of K43 and K32. The regulated genes in both K43 and H43 brains showed an outstanding inverse coordination with the levels of expression of Cx43 in W brain, indicating that the regulated genes are largely predictable from their co-variance with Cx43 in the wildtype samples. These findings lead to the hypothesis that connexin expression may represent a central node in the regulation of gene expression patterns in brain.
Keywords: Connexin43; Connexin32; Connexin43 null mouse; Connexin32 null mouse; Connexin43 heterozygous mouse; Gene expression
Gap junctional communication in tissue inflammation and repair by Marc Chanson; Jean-Paul Derouette; Isabelle Roth; Bernard Foglia; Isabelle Scerri; Tecla Dudez; Brenda R. Kwak (pp. 197-207).
Local injury induces a complex orchestrated response to stimulate healing of injured tissues, cellular regeneration and phagocytosis. Practically, inflammation is defined as a defense process whereby fluid and white blood cells accumulate at a site of injury. The balance of cytokines, chemokines, and growth factors is likely to play a key role in regulating important cell functions such as migration, proliferation, and matrix synthesis during the process of inflammation. Hence, the initiation, maintenance, and resolution of innate responses depend upon cellular communication. A process similar to tissue repair and subsequent scarring is found in a variety of fibrotic diseases. This may occur in a single organ such as liver, kidneys, pancreas, lung, skin, and heart, but fibrosis may also have a more generalized distribution such as in atherosclerosis. The purpose of this review is to summarize recent advances on the contribution of gap junction-mediated intercellular communication in the modulation of the inflammatory response and tissue repair.
Keywords: Gap junction; Connexin; Inflammation; Wound healing; Tissue repair
Gap junction- and hemichannel-independent actions of connexins by Jean X. Jiang; Sumin Gu (pp. 208-214).
Connexins have been known to be the protein building blocks of gap junctions and mediate cell–cell communication. In contrast to the conventional dogma, recent evidence suggests that in addition to forming gap junction channels, connexins possess gap junction-independent functions. One important gap junction-independent function for connexins is to serve as the major functional component for hemichannels, the un-apposed halves of gap junctions. Hemichannels, as independent functional units, play roles that are different from that of gap junctions in the cell. The other functions of connexins appear to be gap junction- and hemichannel-independent. Published studies implicate the latter functions of connexins in cell growth, differentiation, tumorigenicity, injury, and apoptosis, although the mechanistic aspects of these actions remain largely unknown. In this review, gap junction- and hemichannel-independent functions of connexins are summarized, and the molecular mechanisms underlying these connexin functions are speculated and discussed.
Keywords: Gap junction- and hemichannel-independent; Connexin; Cell proliferation; Tumorigenicity; Cell differentiation
Connexin-based gap junction hemichannels: Gating mechanisms by Juan C. Sáez; Mauricio A. Retamal; Daniel Basilio; Feliksas F. Bukauskas; Michael V.L. Bennett (pp. 215-224).
Connexins (Cxs) form hemichannels and gap junction channels. Each gap junction channel is composed of two hemichannels, also termed connexons, one from each of the coupled cells. Hemichannels are hexamers assembled in the ER, the Golgi, or a post Golgi compartment. They are transported to the cell surface in vesicles and inserted by vesicle fusion, and then dock with a hemichannel in an apposed membrane to form a cell–cell channel. It was thought that hemichannels should remain closed until docking with another hemichannel because of the leak they would provide if their permeability and conductance were like those of their corresponding cell–cell channels. Now it is clear that hemichannels formed by a number of different connexins can open in at least some cells with a finite if low probability, and that their opening can be modulated under various physiological and pathological conditions. Hemichannels open in different kinds of cells in culture with conductance and permeability properties predictable from those of the corresponding gap junction channels. Cx43 hemichannels are preferentially closed in cultured cells under resting conditions, but their open probability can be increased by the application of positive voltages and by changes in protein phosphorylation and/or redox state. In addition, increased activity can result from the recruitment of hemichannels to the plasma membrane as seen in metabolically inhibited astrocytes. Mutations of connexins that increase hemichannel open probability may explain cellular degeneration in several hereditary diseases. Taken together, the data indicate that hemichannels are gated by multiple mechanisms that independently or cooperatively affect their open probability under physiological as well as pathological conditions.
Keywords: Connexon; Redox potential; Protein phosphorylation
Innexins: members of an evolutionarily conserved family of gap-junction proteins by Pauline Phelan (pp. 225-245).
Gap junctions are clusters of intercellular channels that provide cells, in all metazoan organisms, with a means of communicating directly with their neighbours. Surprisingly, two gene families have evolved to fulfil this fundamental, and highly conserved, function. In vertebrates, gap junctions are assembled from a large family of connexin proteins. Innexins were originally characterized as the structural components of gap junctions in Drosophila, an arthropod, and the nematode Caenorhabditis elegans. Since then, innexin homologues have been identified in representatives of the other major invertebrate phyla and in insect-associated viruses. Intriguingly, functional innexin homologues have also been found in vertebrate genomes. These studies have informed our understanding of the molecular evolution of gap junctions and have greatly expanded the numbers of model systems available for functional studies. Genetic manipulation of innexin function in relatively simple cellular systems should speed progress not only in defining the importance of gap junctions in a variety of biological processes but also in elucidating the mechanisms by which they act.
Keywords: Innexin; Connexin; Gap junction; Intercellular channel; Drosophila; Caenorhabditis elegans