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Acta Physiologica (Oxford, England) May 2022Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, and dysregulated proteolytic activity can result in... (Review)
Review
Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, and dysregulated proteolytic activity can result in pathogenesis. In this review, we focus on a subclass of membrane-bound and soluble proteases that are defined as channel-activating proteases (CAPs), since they induce Na ion transport through an autocrine mechanism when co-expressed with the highly amiloride-sensitive epithelial sodium channel (ENaC) in Xenopus oocytes. These experiments first identified CAP1 (channel-activating protease 1, prostasin) followed by CAP2 (channel-activating protease 2, TMPRSS4) and CAP3 (channel-activating protease 3, matriptase) as in vitro mediators of ENaC current. Since then, more serine-, cysteine- and metalloproteases were confirmed as in vitro CAPs that potentially cleave and regulate ENaC, and thus this nomenclature was not further followed, but is accepted as functional term or alias. The precise mechanism of ENaC modulation by proteases has not been fully elucidated. Studies in organ-specific protease knockout models revealed evidence for their role in increasing ENaC activity, although the proteases responsible for ENaC activation are yet to be identified. We summarize recent findings in animal models of these CAPs with respect to their implication in ENaC activation. We discuss the consequences of dysregulated CAPs underlying epithelial phenotypes in pathophysiological conditions, and the role of selected protease inhibitors. We believe that these proteases may present interesting therapeutic targets for diseases with aberrant sodium homoeostasis.
Topics: Amiloride; Animals; Epithelial Sodium Channels; Ion Transport; Peptide Hydrolases; Sodium
PubMed: 35276025
DOI: 10.1111/apha.13811 -
Nature Cell Biology Jun 2022Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions and water across their membranes. Macropinocytosis, a...
Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions and water across their membranes. Macropinocytosis, a ubiquitous form of endocytosis of particular importance for immune and cancer cells, generates large vacuoles that can be followed optically. Shrinkage of macrophage macropinosomes depends on TPC-mediated Na efflux and Cl exit through unknown channels. Relieving osmotic pressure facilitates vesicle budding, positioning osmotic shrinkage upstream of vesicular sorting and trafficking. Here we identify the missing macrophage Cl channel as the proton-activated Cl channel ASOR/TMEM206. ASOR activation requires Na-mediated depolarization and luminal acidification by redundant transporters including H-ATPases and CLC 2Cl/H exchangers. As corroborated by mathematical modelling, feedback loops requiring the steep voltage and pH dependencies of ASOR and CLCs render vacuole resolution resilient towards transporter copy numbers. TMEM206 disruption increased albumin-dependent survival of cancer cells. Our work suggests a function for the voltage and pH dependence of ASOR and CLCs, provides a comprehensive model for ion-transport-dependent vacuole maturation and reveals biological roles of ASOR.
Topics: Anions; Chloride Channels; Hydrogen-Ion Concentration; Ion Transport; Protons
PubMed: 35590106
DOI: 10.1038/s41556-022-00912-0 -
International Journal of Molecular... Jan 2022The TMEM16A/anoctamin-1 calcium-activated chloride channel (CaCC) contributes to a range of vital functions, such as the control of vascular tone and epithelial ion... (Review)
Review
The TMEM16A/anoctamin-1 calcium-activated chloride channel (CaCC) contributes to a range of vital functions, such as the control of vascular tone and epithelial ion transport. The channel is a founding member of a family of 10 proteins (TMEM16x) with varied functions; some members (i.e., TMEM16A and TMEM16B) serve as CaCCs, while others are lipid scramblases, combine channel and scramblase function, or perform additional cellular roles. TMEM16x proteins are typically activated by agonist-induced Ca release evoked by G-protein-coupled receptor (GPCR) activation; thus, TMEM16x proteins link Ca-signalling with cell electrical activity and/or lipid transport. Recent studies demonstrate that a range of other cellular factors-including plasmalemmal lipids, pH, hypoxia, ATP and auxiliary proteins-also control the activity of the TMEM16A channel and its paralogues, suggesting that the TMEM16x proteins are effectively polymodal sensors of cellular homeostasis. Here, we review the molecular pathophysiology, structural biology, and mechanisms of regulation of TMEM16x proteins by multiple cellular factors.
Topics: Animals; Anoctamin-1; Anoctamins; Biological Transport; Cell Membrane; Chloride Channels; Humans; Ion Transport; Phospholipid Transfer Proteins
PubMed: 35163502
DOI: 10.3390/ijms23031580 -
Journal of Cystic Fibrosis : Official... Mar 2020Mutations associated with cystic fibrosis (CF) have complex effects on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common CF... (Review)
Review
Mutations associated with cystic fibrosis (CF) have complex effects on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common CF mutation, F508del, disrupts the processing to and stability at the plasma membrane and function as a Cl channel. CFTR is surrounded by a dynamic network of interacting components, referred to as the CFTR Functional Landscape, that impact its synthesis, folding, stability, trafficking and function. CFTR interacting proteins can be manipulated by functional genomic approaches to rescue the trafficking and functional defects characteristic of CF. Here we review recent efforts to elucidate the impact of genetic variation on the ability of the nascent CFTR polypeptide to interact with the proteostatic environment. We also provide an overview of how specific components of this protein network can be modulated to rescue the trafficking and functional defects associated with the F508del variant of CFTR. The identification of novel proteins playing key roles in the processing of CFTR could pave the way for their use as novel therapeutic targets to provide synergistic correction of mutant CFTR for the greater benefit of individuals with CF.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Therapy; Humans; Ion Transport; Membrane Transport Modulators; Mutation; Proteostasis
PubMed: 31680043
DOI: 10.1016/j.jcf.2019.10.017 -
The New Phytologist Jan 2021The coordinated control of ion transport across the two major membranes of differentiated plant cells, the plasma and the vacuolar membranes, is fundamental in cell... (Review)
Review
The coordinated control of ion transport across the two major membranes of differentiated plant cells, the plasma and the vacuolar membranes, is fundamental in cell physiology. The stomata responses to the fluctuating environmental conditions are an illustrative example. Indeed, they rely on the coordination of ion fluxes between the different cell compartments. The cytosolic environment, which is an interface between intracellular compartments, and the activity of the ion transporters localised in the different membranes influence one each other. Here we analyse the molecular mechanisms connecting and modulating the transport processes at both the plasma and the vacuolar membranes of guard cells.
Topics: Arabidopsis; Biological Transport; Cell Membrane; Ion Transport; Vacuoles
PubMed: 33007120
DOI: 10.1111/nph.16983 -
Journal of Cystic Fibrosis : Official... Nov 2017Cystic fibrosis (CF, mucoviscidosis) is caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), which is a chloride and bicarbonate... (Review)
Review
BACKGROUND
Cystic fibrosis (CF, mucoviscidosis) is caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), which is a chloride and bicarbonate channel necessary for fluid secretion and extracellular alkalization. For a long time, research concentrated on abnormal Cl and Na transport, but neglected bicarbonate as a crucial factor in CF.
METHODS
The present short review reports early findings as well as recent insights into the role of CFTR for bicarbonate transport and its defects in CF.
RESULTS
The available data indicate impaired bicarbonate transport not only in pancreas, intestine, airways, and reproductive organs, but also in salivary glands, sweat duct and renal tubular epithelial cells. Defective bicarbonate transport is closely related to the impaired mucus properties and mucus blocking in secretory organs of CF patients, causing the life threatening lung disease.
CONCLUSIONS
Apart from the devastating lung disease, abrogated bicarbonate transport also leads to many other organ dysfunctions, which are outlined in the present review.
Topics: Bicarbonates; Chloride-Bicarbonate Antiporters; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Ion Transport; Mucus
PubMed: 28732801
DOI: 10.1016/j.jcf.2017.06.005 -
Neuron Sep 2015Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of... (Review)
Review
Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of touch and hearing, and the unconscious sensation of blood flow. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels.
Topics: Animals; Humans; Ion Channel Gating; Ion Channels; Ion Transport; Mechanotransduction, Cellular; Sensation; Touch
PubMed: 26402601
DOI: 10.1016/j.neuron.2015.08.032 -
Journal of Biological Inorganic... Dec 2019Copper (Cu) plays an essential role in the development and function of the brain. In humans, genetic disorders of Cu metabolism may cause either severe Cu deficiency... (Review)
Review
Copper (Cu) plays an essential role in the development and function of the brain. In humans, genetic disorders of Cu metabolism may cause either severe Cu deficiency (Menkes disease) or excessive Cu accumulation (Wilson disease) in the brain tissue. In either case, the loss of Cu homeostasis results in catecholamine misbalance, abnormal myelination of neurons, loss of normal brain architecture, and a spectrum of neurologic and/or psychiatric manifestations. Several metabolic processes have been identified as particularly sensitive to Cu dis-homeostasis. This review focuses on the role of Cu in noradrenergic neurons and summarizes the current knowledge of mechanisms that maintain Cu homeostasis in these cells. The impact of Cu misbalance on catecholamine metabolism and functioning of noradrenergic system is discussed.
Topics: Adrenergic Neurons; Animals; Catecholamines; Copper; Homeostasis; Humans; Ion Transport; Locus Coeruleus
PubMed: 31691104
DOI: 10.1007/s00775-019-01737-3 -
Nature Structural & Molecular Biology Jul 2023Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have...
Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have general universal features. However, elucidation of such mechanisms is a challenge. It requires true-atomic-resolution structures of all key proton-conducting states. Here we present a comprehensive function-structure study of a light-driven bacterial inward proton pump, xenorhodopsin, from Bacillus coahuilensis in all major proton-conducting states. The structures reveal that proton translocation is based on proton wires regulated by internal gates. The wires serve as both selectivity filters and translocation pathways for protons. The cumulative results suggest a general concept of proton translocation. We demonstrate the use of serial time-resolved crystallography at a synchrotron source with sub-millisecond resolution for rhodopsin studies, opening the door for principally new applications. The results might also be of interest for optogenetics since xenorhodopsins are the only alternative tools to fire neurons.
Topics: Protons; Proton Pumps; Ion Transport
PubMed: 37386213
DOI: 10.1038/s41594-023-01020-9 -
Journal of Molecular Biology Jan 2015Ion channels facilitate the passive movement of ions down an electrochemical gradient and across lipid bilayers in cells. This phenomenon is essential for life and... (Review)
Review
Ion channels facilitate the passive movement of ions down an electrochemical gradient and across lipid bilayers in cells. This phenomenon is essential for life and underlies many critical homeostatic processes in cells. Ion channels are diverse and differ with respect to how they open and close (gating) and to their ionic conductance/selectivity (permeation). Fundamental understanding of ion channel structure-function mechanisms, their physiological roles, how their dysfunction leads to disease, their utility as biosensors, and development of novel molecules to modulate their activity are important and active research frontiers. In this review, we focus on ion channel engineering approaches that have been applied to investigate these aspects of ion channel function, with a major emphasis on voltage-gated ion channels.
Topics: Animals; Humans; Ion Channels; Ion Transport; Protein Engineering
PubMed: 25205552
DOI: 10.1016/j.jmb.2014.09.001