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Role of Cell-to-Cell Coupling in Control of Myometrial Contractility and Labor
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Gap junctions consist of pores that connect the interiors of two cells (Figure 6). The pore allows passage of neutral and charged molecules to move between cells. The pores are composed of proteins, termed connexins,4 which span the plasma membranes to form a channel. The gap junction proteins have been cloned and antibodies have been prepared to the connexins. In the myometrium a 43-Kdalton protein, termed connexin 43, is thought to be the major component of the gap junction. Connexin 43 is also found in other tissues, including cardiac cells, where it is thought to be required for synchronizing cardiac contractility.4 Connexin 43 is a protein composed of 382 amino acids with two serine residues that may be phosphorylated (Figure 7). Each gap junction can be made up from a few to thousands of channels and each channel is constructed from a group of six connexin proteins, a hemichannel, in one cell aligned symmetrically with six connexins in the adjacent connected cell. The two hemichannels each have a gate, so that each cell can functionally regulate conductance. In some cases the state of phosphorylation has been correlated with changes in functional states of gap junctional communication.80 Phosphorylation of some types of connexins is thought to lead to the open configuration in some cells, whereas the dephosphorylated form of the same connexin is associated with the open state in other cells.
Pathophysiology of neurogenic detrusor overactivity
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Alexandra McPencow, Toby C. Chai
The contribution to NDO by the myofibroblasts within suburothelial lamina propria of the bladder has also been studied. Investigators have found increased gap junction protein, Cx43 (connexin 43), expression in NDO.11 Gap junction proteins connect membranes between two adjacent cells and allow ions to freely pass between them. Therefore, increased Cx43 could promote NDO by facilitating spread of spontaneous electrical activity to surrounding myofibroblasts. Another junctional protein, cadherin-11, was shown to be upregulated in NDO myofibroblasts.12 Cadherin-11 is a member of the adherens junctional protein family. Adherens junctions (or zona adherens) are proteins that provide structure to adjoining cells. Because both cadherin-11 and Cx43 are co-localized on the myofibroblasts, and both are upregulated in NDO, these investigators theorized that these two proteins might interact to form a functional unit that mediates increased myofibroblast activity in NDO.
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
Enhanced cell proliferation is facilitated by reduced intercellular gap junction communication (35–37). The gap junction is a membrane channel between adjacent cells that is composed of junctional hemichannels, connex-ons, in the cell membranes of communicating cells. Connexons are made up of subunit proteins, connexins, of about 15 different types, which are expressed differently in connexons formed in various tissues. The gap junctions allow transport of hydrophylic molecules of low molecular weight (up to 1 kD). A decrease or loss of connexin expression and gap junction formation occurs often in tumors, particularly connexin 43 (121). Thus, the connexin gene family (CNX) may be considered tumor suppresor genes (122). Also, expression of oncogene-coded kinases that produce connexin phosphorylation downregulates gap-junctional communication.
Challenges faced in developing an ideal chronic wound model
Published in Expert Opinion on Drug Discovery, 2023
Mandy Li Ling Tan, Jiah Shin Chin, Leigh Madden, David L. Becker
An ideal delayed wound model should incorporate key characteristics of human chronic wounds. These include features such as delayed re-epithelialization, hyper thickened non-migratory wound edges with overexpression of the gap junction protein connexin 43, persistent inflammation, elevated ROS levels, alkaline wound environment, excessive ECM degradation at wound edges, disrupted/impaired vasculature and sustained presence of senescent cells (Figure 2). Concurrently, the gene expression profiles of wounds from this model should also be validated to reflect trends similar to human chronic wounds. In particular, expression of pro-inflammatory genes and genes regulating protease activity should be significantly upregulated compared to acute wounds. Conversely, the levels of genes regulating anti-inflammatory cytokines and protease inhibitors should be downregulated. Genes involved in regulating the cell cycle checkpoints would reflect the extent of senescence in the wound. In addition, the clinical relevance of the model could be further improved by including other chronic wound causal factors such as ageing, diabetes and ischemic conditions.
Left Ventricular Reverse Remodeling in Heart Failure: Remission to Recovery
Published in Structural Heart, 2021
Jacinthe Boulet, Mandeep R. Mehra
The association between malignant ventricular arrhythmias and cardiac remodeling has been established through various well-defined mechanisms. Remodeling is associated with prolongation of the action potential, changes in sodium, potassium, and calcium channels, including alterations in the sodium/calcium exchanger.50,51 It also disturbs the gap junctional intercellular communication as evidenced by modification of the normal distribution and labeling intensity of connexin 43, the most prominent gap junction protein expressed in the normal heart.50,51 These alterations may be associated with prolongation of the QT interval and promote early after depolarizations and increase the risk of malignant arrhythmias.50 Remodeling also causes the accumulation of myocardial fibrillar collagen involving the epimysium, perimysium, and endomysium, three connective tissue compartments surrounding muscle bundles (epicardium and endocardium), muscle fibers, and single muscles, respectively. The development of fibrosis through increased collagen content may lead to electrical conduction disorders and arrhythmogenesis, especially reentrant arrhythmias facilitated by activation delays with electrogram fractionation through fibrotic muscles.50,52 Altogether, those changes associated with cardiac remodeling increase the risk of sustained ventricular tachycardia and ventricular fibrillation, thus raising patients’ risk of sudden cardiac death.8,53
Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development
Published in Expert Review of Anticancer Therapy, 2020
Michael Ruff, Sani Kizilbash, Jan Buckner
TMs are connected via connexins, specifically connexin 43. Of note, the expression of connexin 43 is inversely related to the stemness of the tumor cell. Glioma initiating stem cells express very low levels of connexin 43, and when this protein is restored the stem cell phenotype of glioma stem cells is reversed and the self-renewal capacity, resistance to standard therapies and invasive capacity is reduced [51]. The discovery of this pathogenic mechanism has already prompted tremendous excitement and a drive to develop rapid through-put techniques to exploit potential vulnerabilities in astrocytoma and glioblastoma cells. A recent publication of interest detailed targeting connexin 43 via chimeric antigen-receptor T-cell therapy [52]. The teleological explanation for why 1p-19q co-deletion is selected for and seems to remain present upon recurrence is unclear.