scholarly journals Divalent Cation Modulation of Ion Permeation in TMEM16 Proteins

2021 ◽  
Vol 22 (4) ◽  
pp. 2209
Author(s):  
Dung M. Nguyen ◽  
Hwoi Chan Kwon ◽  
Tsung-Yu Chen
Keyword(s):  
Alkaline Earth ◽  
Divalent Cations ◽  
Transmembrane Protein ◽  
Ion Selectivity ◽  
Physiological Role ◽  
Ion Permeation ◽  
Membrane Phospholipids ◽  
Anion Channels ◽  
Head Groups

Intracellular divalent cations control the molecular function of transmembrane protein 16 (TMEM16) family members. Both anion channels (such as TMEM16A) and phospholipid scramblases (such as TMEM16F) in this family are activated by intracellular Ca2+ in the low µM range. In addition, intracellular Ca2+ or Co2+ at mM concentrations have been shown to further potentiate the saturated Ca2+-activated current of TMEM16A. In this study, we found that all alkaline earth divalent cations in mM concentrations can generate similar potentiation effects in TMEM16A when applied intracellularly, and that manipulations thought to deplete membrane phospholipids weaken the effect. In comparison, mM concentrations of divalent cations minimally potentiate the current of TMEM16F but significantly change its cation/anion selectivity. We suggest that divalent cations may increase local concentrations of permeant ions via a change in pore electrostatic potential, possibly acting through phospholipid head groups in or near the pore. Monovalent cations appear to exert a similar effect, although with a much lower affinity. Our findings resolve controversies regarding the ion selectivity of TMEM16 proteins. The physiological role of this mechanism, however, remains elusive because of the nearly constant high cation concentrations in cytosols.

scholarly journals A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition

2021 ◽  
Vol 13 ◽  
Author(s):  
Sampath Kumar ◽  
Sanjay S. Kumar
Keyword(s):  
Experimental Data ◽  
Divalent Cations ◽  
Ion Selectivity ◽  
Gene Families ◽  
Subunit Composition ◽  
Receptor Subunit ◽  
Cation Selectivity ◽  
Subunit Stoichiometry ◽  
Ampa And Nmda Receptors

Glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors are implicated in diverse functions ranging from synaptic plasticity to cell death. They are heterotetrameric proteins whose subunits are derived from multiple distinct gene families. The subunit composition of these receptors determines their permeability to monovalent and/or divalent cations, but it is not entirely clear how this selectivity arises in native and recombinantly-expressed receptor populations. By analyzing the sequence of amino acids lining the selectivity filters within the pore forming membrane helices (M2) of these subunits and by correlating subunit stoichiometry of these receptors with their ability to permeate Na+ and/or Ca2+, we propose here a mathematical model for predicting cation selectivity and permeability in these receptors. The model proposed is based on principles of charge attractivity and charge neutralization within the pore forming region of these receptors; it accurately predicts and reconciles experimental data across various platforms including Ca2+ permeability of GluA2-lacking AMPARs and ion selectivity within GluN3-containing di- and tri-heteromeric NMDARs. Additionally, the model provides insights into biophysical mechanisms regulating cation selectivity and permeability of these receptors and the role of various subunits in these processes.

scholarly journals Structure-guided DNA–DNA attraction mediated by divalent cations

2020 ◽  
Author(s):  
Amit Srivastava ◽  
Raju Timsina ◽  
Seung Heo ◽  
Sajeewa W Dewage ◽  
Serdal Kirmizialtin ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Alkaline Earth ◽  
Divalent Cations ◽  
Random Sequence ◽  
Earth Metal ◽  
Alkaline Earth Metal ◽  
Sequence Dependent ◽  
Phosphate Backbone ◽  
Alkaline Earth Metal Ions

Abstract Probing the role of surface structure in electrostatic interactions, we report the first observation of sequence-dependent dsDNA condensation by divalent alkaline earth metal cations. Disparate behaviors were found between two repeating sequences with 100% AT content, a poly(A)-poly(T) duplex (AA-TT) and a poly(AT)-poly(TA) duplex (AT-TA). While AT-TA exhibits non-distinguishable behaviors from random-sequence genomic DNA, AA-TT condenses in all alkaline earth metal ions. We characterized these interactions experimentally and investigated the underlying principles using computer simulations. Both experiments and simulations demonstrate that AA-TT condensation is driven by non-specific ion–DNA interactions. Detailed analyses reveal sequence-enhanced major groove binding (SEGB) of point-charged alkali ions as the major difference between AA-TT and AT-TA, which originates from the continuous and close stacking of nucleobase partial charges. These SEGB cations elicit attraction via spatial juxtaposition with the phosphate backbone of neighboring helices, resulting in an azimuthal angular shift between apposing helices. Our study thus presents a distinct mechanism in which, sequence-directed surface motifs act with cations non-specifically to enact sequence-dependent behaviors. This physical insight allows a renewed understanding of the role of repeating sequences in genome organization and regulation and offers a facile approach for DNA technology to control the assembly process of nanostructures.

scholarly journals Conserved His-Gly motif of acid-sensing ion channels resides in a reentrant ‘loop’ implicated in gating and ion selectivity

2020 ◽  
Author(s):  
Nate Yoder ◽  
Eric Gouaux
Keyword(s):  
Ion Channels ◽  
Ion Selectivity ◽  
Fear Memory ◽  
Amino Terminus ◽  
Ion Permeation ◽  
Structural Explanation ◽  
Cryo Electron Microscopy ◽  
Acid Sensing Ion Channels ◽  
And Function

ABSTRACTAcid-sensing ion channels (ASICs) are proton-gated members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout central and peripheral nervous systems. The homotrimeric splice variant ASIC1a has been implicated in nociception, fear memory, mood disorders and ischemia. Here we extract full-length chicken ASIC1a (cASIC1a) from cell membranes using styrene maleic acid (SMA) copolymer, yielding structures of ASIC1a channels in both high pH resting and low pH desensitized conformations by single-particle cryo-electron microscopy (cryo-EM). The structures of resting and desensitized channels reveal a reentrant loop at the amino terminus of ASIC1a that includes the highly conserved ‘His-Gly’ (HG) motif. The reentrant loop lines the lower ion permeation pathway and buttresses the ‘Gly-Ala-Ser’ (GAS) constriction, thus providing a structural explanation for the role of the His-Gly dipeptide in the structure and function of ASICs.

scholarly journals Neonatal Lethality of LGR5 Null Mice Is Associated with Ankyloglossia and Gastrointestinal Distension

2004 ◽  
Vol 24 (22) ◽  
pp. 9736-9743 ◽  
Author(s):  
Hiroki Morita ◽  
Sabine Mazerbourg ◽  
Donna M. Bouley ◽  
Ching-Wei Luo ◽  
Kazuhiro Kawamura ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Physiological Role ◽  
Targeted Deletion ◽  
Large N ◽  
Neonatal Lethality ◽  
Tract Dilation ◽  
Lgr5 Expression ◽  
Leucine Rich Repeats ◽  
G Protein Coupled

ABSTRACT The physiological role of an orphan G protein-coupled receptor, LGR5, was investigated by targeted deletion of this seven-transmembrane protein containing a large N-terminal extracellular domain with leucine-rich repeats. LGR5 null mice exhibited 100% neonatal lethality characterized by gastrointestinal tract dilation with air and an absence of milk in the stomach. Gross and histological examination revealed fusion of the tongue to the floor of oral cavity in the mutant newborns and immunostaining of LGR5 expression in the epithelium of the tongue and in the mandible of the wild-type embryos. The observed ankyloglossia phenotype provides a model for understanding the genetic basis of this craniofacial defect in humans and an opportunity to elucidate the physiological role of the LGR5 signaling system during embryonic development.

scholarly journals Renal localization and function of the tight junction protein, claudin-19

2007 ◽  
Vol 293 (1) ◽  
pp. F166-F177 ◽  
Author(s):  
Susanne Angelow ◽  
Randa El-Husseini ◽  
Sanae A. Kanzawa ◽  
Alan S. L. Yu
Keyword(s):  
Tight Junction ◽  
Renal Tubule ◽  
Divalent Cations ◽  
Physiological Role ◽  
Hereditary Disease ◽  
Paracellular Transport ◽  
Thick Ascending Limb ◽  
Peripheral Neurons ◽  
Junction Protein

Claudins form a family of transmembrane tight junction proteins that play a key role in control and selectivity of paracellular transport. Mutations in claudin-19, which is expressed in kidney, retina, and myelinated peripheral neurons, were identified in familial hypomagnesemia with hypercalciuria and nephrocalcinosis, a hereditary disease causing renal Mg2+ and Ca2+ wasting. Here, we studied the distribution and possible functional role of claudin-19 in the renal tubule. By immunofluorescence staining of mouse kidney, claudin-19 was found to be expressed at the tight junction of the thick ascending limb of Henle, the major site of paracellular Mg2+ reabsorption, where it colocalized with claudin-16, as well as in the thin ascending limb. The role of claudin-19 in paracellular transport was tested by stable transfection into Madin Darby canine kidney II TetOff cells to generate inducible cell lines. Claudin-19 increased the transepithelial electrical resistance and decreased permeability to monovalent and divalent cations, while anion and urea permeability were not affected. Our data suggest that claudin-19 acts as a selective cation barrier at the tight junction. This would be consistent with its physiological role to electrically seal myelinated peripheral neurons. The normal role of claudin-19 in renal tubule function remains to be determined.

scholarly journals Comparative Study of Cyanobacterial and E. coli RNA Polymerases: Misincorporation, Abortive Transcription, and Dependence on Divalent Cations

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Masahiko Imashimizu ◽  
Kan Tanaka ◽  
Nobuo Shimamoto
Keyword(s):  
Rna Polymerase ◽  
Divalent Cations ◽  
Physiological Role ◽  
Rna Polymerases ◽  
E Coli ◽  
Order Of Magnitude ◽  
Photosynthetic Machinery ◽  
The Difference ◽  
The Cost

If Mg2+ ion is replaced by Mn2+ ion, RNA polymerase tends to misincorporate noncognate nucleotide, which is thought to be one of the reasons for the toxicity of Mn2+ ion. Therefore, most cells have Mn2+ ion at low intracellular concentrations, but cyanobacteria need the ion at a millimolar concentration to maintain photosynthetic machinery. To analyse the mechanism for resistance against the abundant Mn2+ ion, we compared the properties of cyanobacterial and E. coli RNA polymerases. The cyanobacterial enzyme showed a lower level of abortive transcription and less misincorporation than the E. coli enzyme. Moreover, the cyanobacterial enzyme showed a slower rate of the whole elongation by an order of magnitude, paused more frequently, and cleaved its transcript faster in the absence of NTPs. In conclusion, cyanobacterial RNA polymerase maintains the fidelity of transcription against Mn2+ ion by deliberate incorporation of a nucleotide at the cost of the elongation rate. The cyanobacterial and the E. coli enzymes showed different sensitivities to Mg2+ ion, and the physiological role of the difference is also discussed.

scholarly journals The His-Gly motif of acid-sensing ion channels resides in a reentrant ‘loop’ implicated in gating and ion selectivity

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Nate Yoder ◽  
Eric Gouaux
Keyword(s):  
Ion Channels ◽  
Ion Selectivity ◽  
Fear Memory ◽  
Amino Terminus ◽  
Ion Permeation ◽  
Structural Explanation ◽  
Cryo Electron Microscopy ◽  
Acid Sensing Ion Channels ◽  
And Function

Acid-sensing ion channels (ASICs) are proton-gated members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout the central and peripheral nervous systems. The homotrimeric splice variant ASIC1a has been implicated in nociception, fear memory, mood disorders and ischemia. Here, we extract full-length chicken ASIC1 (cASIC1) from cell membranes using styrene maleic acid (SMA) copolymer, elucidating structures of ASIC1 channels in both high pH resting and low pH desensitized conformations by single-particle cryo-electron microscopy (cryo-EM). The structures of resting and desensitized channels reveal a reentrant loop at the amino terminus of ASIC1 that includes the highly conserved ‘His-Gly’ (HG) motif. The reentrant loop lines the lower ion permeation pathway and buttresses the ‘Gly-Ala-Ser’ (GAS) constriction, thus providing a structural explanation for the role of the His-Gly dipeptide in the structure and function of ASICs.

scholarly journals TMEM16A calcium-activated chloride currents in supporting cells of the mouse olfactory epithelium

2019 ◽  
Vol 151 (7) ◽  
pp. 954-966 ◽  
Author(s):  
Tiago Henriques ◽  
Emilio Agostinelli ◽  
Andres Hernandez-Clavijo ◽  
Devendra Kumar Maurya ◽  
Jason R. Rock ◽  
...  
Keyword(s):  
Olfactory Epithelium ◽  
Olfactory System ◽  
Purinergic Receptors ◽  
Ion Selectivity ◽  
Ionic Composition ◽  
Physiological Role ◽  
Apical Surface ◽  
Supporting Cells ◽  
Sustentacular Cells

Glial-like supporting (or sustentacular) cells are important constituents of the olfactory epithelium that are involved in several physiological processes such as production of endocannabinoids, insulin, and ATP and regulation of the ionic composition of the mucus layer that covers the apical surface of the olfactory epithelium. Supporting cells express metabotropic P2Y purinergic receptors that generate ATP-induced Ca2+ signaling through the activation of a PLC-mediated cascade. Recently, we reported that a subpopulation of supporting cells expresses also the Ca2+-activated Cl− channel TMEM16A. Here, we sought to extend our understanding of a possible physiological role of this channel in the olfactory system by asking whether Ca2+ can activate Cl− currents mediated by TMEM16A. We use whole-cell patch-clamp analysis in slices of the olfactory epithelium to measure dose–response relations in the presence of various intracellular Ca2+ concentrations, ion selectivity, and blockage. We find that knockout of TMEM16A abolishes Ca2+-activated Cl− currents, demonstrating that TMEM16A is essential for these currents in supporting cells. Also, by using extracellular ATP as physiological stimuli, we found that the stimulation of purinergic receptors activates a large TMEM16A-dependent Cl− current, indicating a possible role of TMEM16A in ATP-mediated signaling. Altogether, our results establish that TMEM16A-mediated currents are functional in olfactory supporting cells and provide a foundation for future work investigating the precise physiological role of TMEM16A in the olfactory system.

scholarly journals The role of basigin in reproduction

Reproduction ◽  
2020 ◽  
Vol 159 (2) ◽  
pp. R97-R109 ◽  
Author(s):  
Kailiang Li ◽  
Romana A Nowak
Keyword(s):  
Transmembrane Protein ◽  
Cell Metabolism ◽  
Physiological Role ◽  
Model Systems ◽  
Vascular Endothelial ◽  
Potent Inducer ◽  
Important Regulator ◽  
Males And Females ◽  
Endothelial Growth Factor

Basigin is a highly glycosylated transmembrane protein that was originally identified as a product of tumor cells. Basigin is a potent inducer of matrix metalloproteinases (MMPs) and angiogenic factors such as vascular endothelial growth factor (VEGF). Basigin is also a chaperone protein for specific metabolite transporters in the plasma cell membrane such as the monocarboxylate transporters and is an important regulator of cell metabolism. Studies in reproductive model systems have demonstrated that basigin is expressed in the testis, ovary, uterus and placenta and is necessary for normal fertility in both males and females. Overexpression of basigin is associated with reproductive diseases including uterine leiomyomas and endometriosis. This review presents an overview of the literature regarding the physiological role of basigin in reproductive tissues and the mechanistic pathways involved in its actions.

scholarly journals The role of membrane phospholipids in the interaction of ribosomes with endoplasmic-reticulum membrane (Short Communication)

1973 ◽  
Vol 132 (3) ◽  
pp. 637-640 ◽  
Author(s):  
S. Jothy ◽  
S. Tay ◽  
H. Simpkins
Keyword(s):  
Endoplasmic Reticulum ◽  
Short Communication ◽  
Endoplasmic Reticulum Membrane ◽  
Membrane Phospholipids ◽  
Binding Process ◽  
Head Groups ◽  
Membrane Components

It is shown that the ionic head groups of the membrane phospholipids cannot be solely responsible for the attachment of the ribosome and that other membrane components must also be involved in the binding process.

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