CLC-0 and CFTR: Chloride Channels Evolved From Transporters

2008 ◽  
Vol 88 (2) ◽  
pp. 351-387 ◽  
Author(s):  
Tsung-Yu Chen ◽  
Tzyh-Chang Hwang
Keyword(s):  
Ion Channels ◽  
Membrane Transport ◽  
Chloride Channels ◽  
Transport Proteins ◽  
Transmembrane Conductance Regulator ◽  
Protein Families ◽  
Transmembrane Conductance ◽  
Functional Studies ◽  
Membrane Transport Proteins ◽  
Cystic Fibrosis Transmembrane

CLC-0 and cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels play important roles in Cl− transport across cell membranes. These two proteins belong to, respectively, the CLC and ABC transport protein families whose members encompass both ion channels and transporters. Defective function of members in these two protein families causes various hereditary human diseases. Ion channels and transporters were traditionally viewed as distinct entities in membrane transport physiology, but recent discoveries have blurred the line between these two classes of membrane transport proteins. CLC-0 and CFTR can be considered operationally as ligand-gated channels, though binding of the activating ligands appears to be coupled to an irreversible gating cycle driven by an input of free energy. High-resolution crystallographic structures of bacterial CLC proteins and ABC transporters have led us to a better understanding of the gating properties for CLC and CFTR Cl− channels. Furthermore, the joined force between structural and functional studies of these two protein families has offered a unique opportunity to peek into the evolutionary link between ion channels and transporters. A promising byproduct of this exercise is a deeper mechanistic insight into how different transport proteins work at a fundamental level.

scholarly journals State-dependent Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels by a Novel Peptide Toxin

2007 ◽  
Vol 282 (52) ◽  
pp. 37545-37555 ◽  
Author(s):  
Matthew D. Fuller ◽  
Christopher H. Thompson ◽  
Zhi-Ren Zhang ◽  
Cody S. Freeman ◽  
Eszter Schay ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channels ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
State Dependent ◽  
Dependent Inhibition ◽  
Peptide Toxin ◽  
Cystic Fibrosis Transmembrane

Characterizing diverse orthologues of the cystic fibrosis transmembrane conductance regulator protein for structural studies

2015 ◽  
Vol 43 (5) ◽  
pp. 894-900 ◽  
Author(s):  
Naomi L. Pollock ◽  
Tracy L. Rimington ◽  
Robert C. Ford
Keyword(s):  
Cystic Fibrosis ◽  
Structural Data ◽  
Transmembrane Conductance Regulator ◽  
Loss Of Function ◽  
Transmembrane Conductance ◽  
Functional Studies ◽  
Regulator Protein ◽  
Organ Systems ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane

As an ion channel, the cystic fibrosis transmembrane conductance regulator (CFTR) protein occupies a unique niche within the ABC family. Orthologues of CFTR are extant throughout the animal kingdom from sharks to platypods to sheep, where the osmoregulatory function of the protein has been applied to differing lifestyles and diverse organ systems. In humans, loss-of-function mutations to CFTR cause the disease cystic fibrosis, which is a significant health burden in populations of white European descent. Orthologue screening has proved fruitful in the pursuit of high-resolution structural data for several membrane proteins, and we have applied some of the princples developed in previous studies to the expression and purification of CFTR. We have overexpressed this protein, along with evolutionarily diverse orthologues, in Saccharomyces cerevisiae and developed a purification to isolate it in quantities sufficient for structural and functional studies.

Ion homeostasis, channels, and transporters: an update on cellular mechanisms

2004 ◽  
Vol 28 (4) ◽  
pp. 143-154 ◽  
Author(s):  
George R. Dubyak
Keyword(s):  
Ion Channels ◽  
Subcellular Localization ◽  
Ion Transport ◽  
Membrane Transport ◽  
Cell Biology ◽  
Functional Characterization ◽  
Transport Proteins ◽  
Transport Protein ◽  
Membrane Transport Proteins ◽  
Functional Analyses

The steady-state maintenance of highly asymmetric concentrations of the major inorganic cations and anions is a major function of both plasma membranes and the membranes of intracellular organelles. Homeostatic regulation of these ionic gradients is critical for most functions. Due to their charge, the movements of ions across biological membranes necessarily involves facilitation by intrinsic membrane transport proteins. The functional characterization and categorization of membrane transport proteins was a major focus of cell physiological research from the 1950s through the 1980s. On the basis of these functional analyses, ion transport proteins were broadly divided into two classes: channels and carrier-type transporters (which include exchangers, cotransporters, and ATP-driven ion pumps). Beginning in the mid-1980s, these functional analyses of ion transport and homeostasis were complemented by the cloning of genes encoding many ion channels and transporter proteins. Comparison of the predicted primary amino acid sequences and structures of functionally similar ion transport proteins facilitated their grouping within families and superfamilies of structurally related membrane proteins. Postgenomics research in ion transport biology increasingly involves two powerful approaches. One involves elucidation of the molecular structures, at the atomic level in some cases, of model ion transport proteins. The second uses the tools of cell biology to explore the cell-specific function or subcellular localization of ion transport proteins. This review will describe how these approaches have provided new, and sometimes surprising, insights regarding four major questions in current ion transporter research. 1) What are the fundamental differences between ion channels and ion transporters? 2) How does the interaction of an ion transport protein with so-called adapter proteins affect its subcellular localization or regulation by various intracellular signal transduction pathways? 3) How does the specific lipid composition of the local membrane microenvironment modulate the function of an ion transport protein? 4) How can the basic functional properties of a ubiquitously expressed ion transport protein vary depending on the cell type in which it is expressed?

scholarly journals Expression of ENaC subunits, chloride channels, and aquaporins in ovine fetal lung: ontogeny of expression and effects of altered fetal cortisol concentrations

2009 ◽  
Vol 297 (2) ◽  
pp. R453-R461 ◽  
Author(s):  
Nathan M. Jesse ◽  
Jarret McCartney ◽  
Xiaodi Feng ◽  
Elaine M. Richards ◽  
Charles E. Wood ◽  
...  
Keyword(s):  
Ion Channels ◽  
Chloride Channels ◽  
Fetal Lung ◽  
Fluid Secretion ◽  
Late Gestation ◽  
Transmembrane Conductance Regulator ◽  
Ontogenetic Changes ◽  
Transmembrane Conductance ◽  
Fetal Sheep ◽  
Ovine Fetal

Transition of the epithelium of the fetal lung from fluid secretion to fluid reabsorption requires changes in the expression of ion channels. Corticosteroids regulate expression of several of these channels, including the epithelium sodium channel (ENaC) subunits and aquaporins (AQP). We investigated the ontogenetic changes in these ion channels in the ovine fetal lung during the last half of gestation, a time of increasing adrenal maturation. Expression of the mRNAs for the chloride channels, cystic fibrosis transmembrane conductance regulator (CFTR), and chloride channel 2 (CLCN2) decreased with age. Expression of mRNAs for AQP1, AQP5, and for subunits of ENaC (α, β, γ) increased with age. In the fetal sheep the expression of ENaCβ mRNA was dramatically higher than the expression of ENaCα or ENaCγ, but expression of ENaCβ protein decreased with maturation, although the ratio of the mature (112 kDa) to immature (102 kDa) ENaCβ protein increased with age, particularly in the membrane fraction. In contrast, ENaCα mRNA and protein both increase with maturation, and the mature form of ENaCα (68 kDa) predominates at all ages. A modest increase in fetal cortisol, within the range expected to occur naturally in late gestation but prior to active labor, increased ENaCα mRNA but not ENaCβ, ENaCγ, or AQP mRNAs. We conclude that in the ovine fetal lung, appearance of functional sodium channels is associated with induction of ENACα and ENaCγ, and that ENaCα expression may be induced by even small, preterm increases in fetal cortisol.

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