The Journey Across: Dynamics and Regulation of Transmembrane Transport

A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Dynamics and Computation".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 9710

Special Issue Editors


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Guest Editor
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
Interests: transmembrane transport; membrane protein; membrane transport

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Guest Editor
Department of Chemistry, Columbia University, Manhattan, NY 10027, USA
Interests: dynamic trafficking of proteins facilitating transport

Special Issue Information

Dear Colleagues,

The temporally and spatially precise control of intracellular steady-state levels of solutes such as ions and small molecules is essential in myriad vital physiological processes. The passage of solutes across the semipermeable plasma membrane is enabled by a variety of passive and active transport systems, ranging from voltage-gated potassium ion (Kv) channels to sodium-coupled neurotransmitter symporters (e.g., dopamine transporter, DAT) to adenosine triphosphate (ATP)-binding cassette transporters. Progress in elucidating the molecular mechanisms underlying transport rate, specificity, and selectivity of these systems has been more rapid than ever due to methodological innovations in cryogenic electron microscopy, super-resolution microscopy, atomic force microscopy, and molecular modeling. Particular emphasis has been placed on investigating the mechanistic consequences of structural diversity and biophysical phenotype heterogeneity of the plasma membrane on solute transport.

The aim of this Special Issue is to highlight recent progress in probing the dynamics and regulation of transmembrane solute transport via experimental and computational approaches. We anticipate that this Special Issue will effectively integrate and leverage complementary insights obtained at different spatiotemporal scales to describe the molecular complexity of solute transport across the plasma membrane. Original research articles and comprehensive reviews are cordially invited.

Dr. Oleg Kovtun
Dr. Jerry C. Chang
Guest Editors

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Keywords

  • transmembrane transport
  • membrane transporters
  • ion channels
  • regulation of transmembrane transport
  • dynamics of transmembrane transport

Published Papers (6 papers)

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Research

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18 pages, 3431 KiB  
Article
Interactions of the Kv1.1 Channel with Peptide Pore Blockers: A Fluorescent Analysis on Mammalian Cells
by Nikita A. Orlov, Elena V. Kryukova, Anastasia V. Efremenko, Sergey A. Yakimov, Victoria A. Toporova, Mikhail P. Kirpichnikov, Oksana V. Nekrasova and Alexey V. Feofanov
Membranes 2023, 13(7), 645; https://doi.org/10.3390/membranes13070645 - 4 Jul 2023
Viewed by 993
Abstract
The voltage-gated potassium channel Kv1.1, which is abundant in the CNS and peripheral nervous system, controls neuronal excitability and neuromuscular transmission and mediates a number of physiological functions in non-excitable cells. The development of some diseases is accompanied by changes in the expression [...] Read more.
The voltage-gated potassium channel Kv1.1, which is abundant in the CNS and peripheral nervous system, controls neuronal excitability and neuromuscular transmission and mediates a number of physiological functions in non-excitable cells. The development of some diseases is accompanied by changes in the expression level and/or activity of the channels in particular types of cells. To meet the requirements of studies related to the expression and localization of the Kv1.1 channels, we report on the subnanomolar affinity of hongotoxin 1 N-terminally labeled with Atto 488 fluorophore (A-HgTx) for the Kv1.1 channel and its applicability for fluorescent imaging of the channel in living cells. Taking into consideration the pharmacological potential of the Kv1.1 channel, a fluorescence-based analytical system was developed for the study of peptide ligands that block the ion conductivity of Kv1.1 and are potentially able to correct abnormal activity of the channel. The system is based on analysis of the competitive binding of the studied compounds and A-HgTx to the mKate2-tagged human Kv1.1 (S369T) channel, expressed in the plasma membrane of Neuro2a cells. The system was validated by measuring the affinities of the known Kv1.1-channel peptide blockers, such as agitoxin 2, kaliotoxin 1, hongotoxin 1, and margatoxin. Peptide pore blocker Ce1, from the venom of the scorpion Centruroides elegans, was shown to possess a nanomolar affinity for the Kv1.1 channel. It is reported that interactions of the Kv1.1 channel with the studied peptide blockers are not affected by the transition of the channel from the closed to open state. The conclusion is made that the structural rearrangements accompanying the channel transition into the open state do not change the conformation of the P-loop (including the selectivity filter) involved in the formation of the binding site of the peptide pore blockers. Full article
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16 pages, 1944 KiB  
Article
Hypo-Osmotic Stress and Pore-Forming Toxins Adjust the Lipid Order in Sheep Red Blood Cell Membranes
by Rose Whiting, Sevio Stanton, Maryna Kucheriava, Aviana R. Smith, Matt Pitts, Daniel Robertson, Jacob Kammer, Zhiyu Li and Daniel Fologea
Membranes 2023, 13(7), 620; https://doi.org/10.3390/membranes13070620 - 25 Jun 2023
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Abstract
Lipid ordering in cell membranes has been increasingly recognized as an important factor in establishing and regulating a large variety of biological functions. Multiple investigations into lipid organization focused on assessing ordering from temperature-induced phase transitions, which are often well outside the physiological [...] Read more.
Lipid ordering in cell membranes has been increasingly recognized as an important factor in establishing and regulating a large variety of biological functions. Multiple investigations into lipid organization focused on assessing ordering from temperature-induced phase transitions, which are often well outside the physiological range. However, particular stresses elicited by environmental factors, such as hypo-osmotic stress or protein insertion into membranes, with respect to changes in lipid status and ordering at constant temperature are insufficiently described. To fill these gaps in our knowledge, we exploited the well-established ability of environmentally sensitive membrane probes to detect intramembrane changes at the molecular level. Our steady state fluorescence spectroscopy experiments focused on assessing changes in optical responses of Laurdan and diphenylhexatriene upon exposure of red blood cells to hypo-osmotic stress and pore-forming toxins at room temperature. We verified our utilized experimental systems by a direct comparison of the results with prior reports on artificial membranes and cholesterol-depleted membranes undergoing temperature changes. The significant changes observed in the lipid order after exposure to hypo-osmotic stress or pore-forming toxins resembled phase transitions of lipids in membranes, which we explained by considering the short-range interactions between membrane components and the hydrophobic mismatch between membrane thickness and inserted proteins. Our results suggest that measurements of optical responses from the membrane probes constitute an appropriate method for assessing the status of lipids and phase transitions in target membranes exposed to mechanical stresses or upon the insertion of transmembrane proteins. Full article
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19 pages, 696 KiB  
Article
An Isotonic Model of Neuron Swelling Based on Co-Transport of Salt and Water
by Reinoud Maex
Membranes 2023, 13(2), 206; https://doi.org/10.3390/membranes13020206 - 7 Feb 2023
Cited by 1 | Viewed by 1230
Abstract
Neurons spend most of their energy building ion gradients across the cell membrane. During energy deprivation the neurons swell, and the concomitant mixing of their ions is commonly assumed to lead toward a Donnan equilibrium, at which the concentration gradients of all permeant [...] Read more.
Neurons spend most of their energy building ion gradients across the cell membrane. During energy deprivation the neurons swell, and the concomitant mixing of their ions is commonly assumed to lead toward a Donnan equilibrium, at which the concentration gradients of all permeant ion species have the same Nernst potential. This Donnan equilibrium, however, is not isotonic, as the total concentration of solute will be greater inside than outside the neurons. The present theoretical paper, in contrast, proposes that neurons follow a path along which they swell quasi-isotonically by co-transporting water and ions. The final neuronal volume on the path is taken that at which the concentration of impermeant anions in the shrinking extracellular space equals that inside the swelling neurons. At this final state, which is also a Donnan equilibrium, all permeant ions can mix completely, and their Nernst potentials vanish. This final state is isotonic and electro-neutral, as are all intermediate states along this path. The path is in principle reversible, and maximizes the work of mixing. Full article
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16 pages, 3976 KiB  
Article
The Optimized Conformation Dynamics of the KcsA Filter as a Probe for Lateral Membrane Effects: A First Principle Based Femto-Sec Resolution MD Study
by Johann Summhammer, Georg Sulyok, Gustav Bernroider and Massimo Cocchi
Membranes 2022, 12(12), 1183; https://doi.org/10.3390/membranes12121183 - 24 Nov 2022
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Abstract
We provide a high resolution, all-atom, femto-second molecular dynamics (MD) simulation of the passage of K+ ions and H2O molecules through the selectivity filter of the KcsA potassium ion channel, based on first principle physical methods. Our results show that [...] Read more.
We provide a high resolution, all-atom, femto-second molecular dynamics (MD) simulation of the passage of K+ ions and H2O molecules through the selectivity filter of the KcsA potassium ion channel, based on first principle physical methods. Our results show that a change in the length of the selectivity filter of as little as 3%, regardless of whether the filter is made longer or shorter, will reduce the K+ ion current by around 50%. In addition, further squeezing or stretching by about 9% can effectively stop the current. Our results demonstrate optimized conformational dynamics that associate an increased mobility of parts in the filter linings with a standard configuration, leading to maximized conduction rates that are highly sensitive to geometrical distortions. We discuss this latter aspect in relation to lateral membrane effects on the filter region of ion channels and the ‘force from lipids’ hypothesis. Full article
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Review

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14 pages, 2975 KiB  
Review
The Potassium Efflux System Kef: Bacterial Protection against Toxic Electrophilic Compounds
by Tim Rasmussen
Membranes 2023, 13(5), 465; https://doi.org/10.3390/membranes13050465 - 27 Apr 2023
Cited by 1 | Viewed by 1329
Abstract
Kef couples the potassium efflux with proton influx in gram-negative bacteria. The resulting acidification of the cytosol efficiently prevents the killing of the bacteria by reactive electrophilic compounds. While other degradation pathways for electrophiles exist, Kef is a short-term response that is crucial [...] Read more.
Kef couples the potassium efflux with proton influx in gram-negative bacteria. The resulting acidification of the cytosol efficiently prevents the killing of the bacteria by reactive electrophilic compounds. While other degradation pathways for electrophiles exist, Kef is a short-term response that is crucial for survival. It requires tight regulation since its activation comes with the burden of disturbed homeostasis. Electrophiles, entering the cell, react spontaneously or catalytically with glutathione, which is present at high concentrations in the cytosol. The resulting glutathione conjugates bind to the cytosolic regulatory domain of Kef and trigger activation while the binding of glutathione keeps the system closed. Furthermore, nucleotides can bind to this domain for stabilization or inhibition. The binding of an additional ancillary subunit, called KefF or KefG, to the cytosolic domain is required for full activation. The regulatory domain is termed K+ transport–nucleotide binding (KTN) or regulator of potassium conductance (RCK) domain, and it is also found in potassium uptake systems or channels in other oligomeric arrangements. Bacterial RosB-like transporters and K+ efflux antiporters (KEA) of plants are homologs of Kef but fulfill different functions. In summary, Kef provides an interesting and well-studied example of a highly regulated bacterial transport system. Full article
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19 pages, 2252 KiB  
Review
The Role of Inorganic Phosphate Transporters in Highly Proliferative Cells: From Protozoan Parasites to Cancer Cells
by Marco Antonio Lacerda-Abreu, Claudia Fernanda Dick and José Roberto Meyer-Fernandes
Membranes 2023, 13(1), 42; https://doi.org/10.3390/membranes13010042 - 29 Dec 2022
Cited by 3 | Viewed by 2151
Abstract
In addition to their standard inorganic phosphate (Pi) nutritional function, Pi transporters have additional roles in several cells, including Pi sensing (the so-called transceptor) and a crucial role in Pi metabolism, where they control several phenotypes, such as virulence in pathogens and tumour [...] Read more.
In addition to their standard inorganic phosphate (Pi) nutritional function, Pi transporters have additional roles in several cells, including Pi sensing (the so-called transceptor) and a crucial role in Pi metabolism, where they control several phenotypes, such as virulence in pathogens and tumour aggressiveness in cancer cells. Thus, intracellular Pi concentration should be tightly regulated by the fine control of intake and storage in organelles. Pi transporters are classified into two groups: the Pi transporter (PiT) family, also known as the Pi:Na+ symporter family; and the Pi:H+ symporter (PHS) family. Highly proliferative cells, such as protozoan parasites and cancer cells, rely on aerobic glycolysis to support the rapid generation of biomass, which is equated with the well-known Warburg effect in cancer cells. In protozoan parasite cells, Pi transporters are strongly associated with cell proliferation, possibly through their action as intracellular Pi suppliers for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Similarly, the growth rate hypothesis (GRH) proposes that the high Pi demands of tumours when achieving accelerated proliferation are mainly due to increased allocation to P-rich nucleic acids. The purpose of this review was to highlight recent advances in understanding the role of Pi transporters in unicellular eukaryotes and tumorigenic cells, correlating these roles with metabolism in these cells. Full article
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