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Biomolecules
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Lipid-Gating and Lipid-Protein Interactions in Ion Channels
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Lipid-Gating and Lipid-Protein Interactions in Ion Channels

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Lipids".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 21615

Special Issue Editors

Prof. Dr. Klaus Groschner

E-Mail Website
Guest Editor
Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6/D04, 8010 Graz, Austria
Interests: ion channels; Ca2+ signaling; TRP proteins; regulatory lipid-protein interactions; membrane micro- and nanodomains; photopharmacology; opto-chemogenetics
Prof. Dr. Christoph Romanin

E-Mail Website1 Website2
Guest Editor
Institute of Biophysics, University of Linz, Gruberstrasse 40, 4020 Linz, Austria
Interests: Ca2+ signalling; CRAC channel; STIM and Orai proteins; electrophysiology; fluorescence microscopy

Special Issue Information

Dear Colleagues,

Ion channels are permeation pathways for the transfer of ions across the lipid barrier of biological membranes. Thereby, channel molecules are a pivotal element of signal transduction in virtually all cell membranes, and essential for the control of cell- and tissue functions. Operation of these signaling proteins is tightly linked to their membrane lipid environment, involving abundant communication pathways between the pore-forming protein complexes and their surrounding lipid bilayer. The impact of lipids and of lipid metabolism on channel function is still incompletely understood and considered to involve a variety of mechanistic concepts, ranging from physical effects of bulk lipid to specific lipid-protein interactions of non-annular lipids, which bind specifically to sites within crevices and clefts of ion channel complexes. Ion channel-lipid communication appears crucially involved in various human pathologies and has become in focus of therapeutic developments. Current progress in high-resolution analysis of channel structures, including the identification of lipid species immersed within pore complexes, along with technological advances allowing for unprecedented insight into lipid-protein interactions, have opened new avenues towards deciphering these key processes of physiology and pathophysiology. The scope of this special issue of Biomolecules is to compile information on timely issues of ion channel-lipid communication, ranging from mechanistic aspects of lipid-gating in ion channels to structural insight into lipid coordination within channel complexes, new approaches for computational modeling of lipid-channel interactions and emerging pathophysiological as well as therapeutic concepts.

Prof. Dr. Klaus Groschner
Prof. Dr. Christoph Romanin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ion channels
  • Lipid gating
  • Ion channel structure
  • Ion channel lipidation
  • Regulatory lipid coordination
  • Lipid-protein interactions
  • Ion channel pharmacology

Published Papers (8 papers)

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Research

Jump to: Review

13 pages, 2353 KiB  
Article
Exploring TRPC3 Interaction with Cholesterol through Coarse-Grained Molecular Dynamics Simulations
by Amy Clarke, Klaus Groschner and Thomas Stockner
Biomolecules 2022, 12(7), 890; https://doi.org/10.3390/biom12070890 - 25 Jun 2022
Cited by 2 | Viewed by 2005
Abstract
Transient receptor potential canonical 3 (TRPC3) channel belongs to the superfamily of transient receptor potential (TRP) channels which mediate Ca2+ influx into the cell. These channels constitute essential elements of cellular signalling and have been implicated in a wide range of diseases. [...] Read more.
Transient receptor potential canonical 3 (TRPC3) channel belongs to the superfamily of transient receptor potential (TRP) channels which mediate Ca2+ influx into the cell. These channels constitute essential elements of cellular signalling and have been implicated in a wide range of diseases. TRPC3 is primarily gated by lipids and its surface expression has been shown to be dependent on cholesterol, yet a comprehensive exploration of its interaction with this lipid has thus far not emerged. Here, through 80 µs of coarse-grained molecular dynamics simulations, we show that cholesterol interacts with multiple elements of the transmembrane machinery of TRPC3. Through our approach, we identify an annular binding site for cholesterol on the pre-S1 helix and a non-annular site at the interface between the voltage-sensor-like domain and pore domains. Here, cholesterol interacts with exposed polar residues and possibly acts to stabilise the domain interface. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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19 pages, 3367 KiB  
Article
TRPV6 Regulation by Cis-22a and Cholesterol
by Christina Humer, Sonja Lindinger, Aline L. Carrel, Christoph Romanin and Carmen Höglinger
Biomolecules 2022, 12(6), 804; https://doi.org/10.3390/biom12060804 - 08 Jun 2022
Cited by 4 | Viewed by 2094
Abstract
The highly calcium-selective transient receptor potential vanilloid-type channel TRPV6 is important for epithelial Ca2+ transport. Proper regulation of the inherently constitutively active TRPV6 channels is intricate in preserving Ca2+ homeostasis, whereby structural and functional data suggest that lipids hold an essential [...] Read more.
The highly calcium-selective transient receptor potential vanilloid-type channel TRPV6 is important for epithelial Ca2+ transport. Proper regulation of the inherently constitutively active TRPV6 channels is intricate in preserving Ca2+ homeostasis, whereby structural and functional data suggest that lipids hold an essential role. Altered expression levels or specific TRPV6 mutations may lead to diseases, hence, TRPV6 represents an interesting target for pharmacological modulation. Recent cryo-EM data identified that the specific TRPV6 blocker cis-22a binds, apart from the pore, to a site within the tetrameric channel that largely matches a lipid binding pocket, LBS-2. Therein, cis-22a may replace a lipid such as cholesterol that is bound in the open state. Based on site-directed mutagenesis and functional recordings, we identified and characterized a series of residues within LBS-2 that are essential for TRPV6 inhibition by cis-22a. Additionally, we investigated the modulatory potential of diverse cholesterol depletion efforts on TRPV6 activity. While LBS-2 mutants exhibited altered maximum currents, slow Ca2+-dependent inactivation (SCDI) as well as less inhibition by cis-22a, TRPV6 activity was resistant to cholesterol depletion. Hence, lipids other than cholesterol may predominate TRPV6 regulation when the channel is expressed in HEK293 cells. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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11 pages, 1655 KiB  
Article
Characterization of DAG Binding to TRPC Channels by Target-Dependent cis–trans Isomerization of OptoDArG
by Hazel Erkan-Candag, Denis Krivic, Mathias A. F. Gsell, Mina Aleksanyan, Thomas Stockner, Rumiana Dimova, Oleksandra Tiapko and Klaus Groschner
Biomolecules 2022, 12(6), 799; https://doi.org/10.3390/biom12060799 - 07 Jun 2022
Cited by 5 | Viewed by 2000
Abstract
Azobenzene-based photochromic lipids are valuable probes for the analysis of ion channel–lipid interactions. Rapid photoisomerization of these molecules enables the analysis of lipid gating kinetics and provides information on lipid sensing. Thermal relaxation of the metastable cis conformation to the trans conformation of [...] Read more.
Azobenzene-based photochromic lipids are valuable probes for the analysis of ion channel–lipid interactions. Rapid photoisomerization of these molecules enables the analysis of lipid gating kinetics and provides information on lipid sensing. Thermal relaxation of the metastable cis conformation to the trans conformation of azobenzene photolipids is rather slow in the dark and may be modified by ligand–protein interactions. Cis photolipid-induced changes in pure lipid membranes as visualized from the morphological response of giant unilamellar vesicles indicated that thermal cis–trans isomerization of both PhoDAG-1 and OptoDArG is essentially slow in the lipid bilayer environment. While the currents activated by cis PhoDAG remained stable upon termination of UV light exposure (dark, UV-OFF), cis OptoDArG-induced TRPC3/6/7 activity displayed a striking isoform-dependent exponential decay. The deactivation kinetics of cis OptoDArG-induced currents in the dark was sensitive to mutations in the L2 lipid coordination site of TRPC channels. We conclude that the binding of cis OptoDArG to TRPC channels promotes transition of cis OptoDArG to the trans conformation. This process is suggested to provide valuable information on DAG–ion channel interactions and may enable highly selective photopharmacological interventions. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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17 pages, 4398 KiB  
Article
Membrane Activity of LL-37 Derived Antimicrobial Peptides against Enterococcus hirae: Superiority of SAAP-148 over OP-145
by Paulina Piller, Heimo Wolinski, Robert A. Cordfunke, Jan Wouter Drijfhout, Sandro Keller, Karl Lohner and Nermina Malanovic
Biomolecules 2022, 12(4), 523; https://doi.org/10.3390/biom12040523 - 30 Mar 2022
Cited by 13 | Viewed by 2323
Abstract
The development of antimicrobial agents against multidrug-resistant bacteria is an important medical challenge. Antimicrobial peptides (AMPs), human cathelicidin LL-37 and its derivative OP-145, possess a potent antimicrobial activity and were under consideration for clinical trials. In order to overcome some of the challenges [...] Read more.
The development of antimicrobial agents against multidrug-resistant bacteria is an important medical challenge. Antimicrobial peptides (AMPs), human cathelicidin LL-37 and its derivative OP-145, possess a potent antimicrobial activity and were under consideration for clinical trials. In order to overcome some of the challenges to their therapeutic potential, a very promising AMP, SAAP-148 was designed. Here, we studied the mode of action of highly cationic SAAP-148 in comparison with OP-145 on membranes of Enterococcus hirae at both cellular and molecular levels using model membranes composed of major constituents of enterococcal membranes, that is, anionic phosphatidylglycerol (PG) and cardiolipin (CL). In all assays used, SAAP-148 was consistently more efficient than OP-145, but both peptides displayed pronounced time and concentration dependences in killing bacteria and performing at the membrane. At cellular level, Nile Red-staining of enterococcal membranes showed abnormalities and cell shrinkage, which is also reflected in depolarization and permeabilization of E. hirae membranes. At the molecular level, both peptides abolished the thermotropic phase transition and induced disruption of PG/CL. Interestingly, the membrane was disrupted before the peptides neutralized the negative surface charge of PG/CL. Our results demonstrate that SAAP-148, which kills bacteria at a significantly lower concentration than OP-145, shows stronger effects on membranes at the cellular and molecular levels. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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Review

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15 pages, 1605 KiB  
Review
STIM Proteins and Regulation of SOCE in ER-PM Junctions
by Moaz Ahmad, Sasirekha Narayanasamy, Hwei Ling Ong and Indu Ambudkar
Biomolecules 2022, 12(8), 1152; https://doi.org/10.3390/biom12081152 - 20 Aug 2022
Cited by 6 | Viewed by 2328
Abstract
ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or [...] Read more.
ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or modulate the lipid levels of both ER and plasma membranes. The ER-PM junctions have come under much scrutiny recently as they serve as hubs for assembling the Ca2+ signaling complexes. This review summarizes: (1) key findings that underlie the abilities of STIM proteins to accumulate in ER-PM junctions; (2) the modulation of Orai/STIM complexes by other components found within the same junction; and (3) how Orai1 channel activation is coordinated and coupled with downstream signaling pathways. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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21 pages, 3295 KiB  
Review
Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels
by Anna Ananchenko, Toka O. K. Hussein, Deepansh Mody, Mackenzie J. Thompson and John E. Baenziger
Biomolecules 2022, 12(6), 814; https://doi.org/10.3390/biom12060814 - 10 Jun 2022
Cited by 7 | Viewed by 3128
Abstract
Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function [...] Read more.
Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC–lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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19 pages, 3457 KiB  
Review
The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels
by Rita Gutorov, Ben Katz, Elisheva Rhodes-Mordov, Rachel Zaguri, Tal Brandwine-Shemmer and Baruch Minke
Biomolecules 2022, 12(3), 382; https://doi.org/10.3390/biom12030382 - 28 Feb 2022
Cited by 2 | Viewed by 2998
Abstract
Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to [...] Read more.
Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the Drosophila TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of Drosophila. Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase Cβ (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into Diacylglycerol (DAG) and Inositol 1, 4,5-trisphosphate (IP3). However, the events required for channel gating downstream of PLC activation are still under debate and led to several hypotheses regarding the mechanisms by which lipids gate the channels. Despite many efforts, compelling evidence of the involvement of DAG accumulation, PIP2 depletion or IP3-mediated Ca2+ release in light activation of the TRP/TRPL channels are still lacking. Exogeneous application of poly unsaturated fatty acids (PUFAs), a product of DAG hydrolysis was demonstrated as an efficient way to activate the Drosophila TRP/TRPL channels. However, compelling evidence for the involvement of PUFAs in physiological light-activation of the TRP/TRPL channels is still lacking. Light-induced mechanical force generation was measured in photoreceptor cells prior to channel opening. This mechanical force depends on PLC activity, suggesting that the enzymatic activity of PLC converting PIP2 into DAG generates membrane tension, leading to mechanical gating of the channels. In this review, we will present the roles of membrane lipids in light activation of Drosophila TRP channels and present the many advantages of this model system in the exploration of TRP channel activation under physiological conditions. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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37 pages, 3070 KiB  
Review
The Role of Lipids in CRAC Channel Function
by Lena Maltan, Ana-Marija Andova and Isabella Derler
Biomolecules 2022, 12(3), 352; https://doi.org/10.3390/biom12030352 - 23 Feb 2022
Cited by 3 | Viewed by 3402
Abstract
The composition and dynamics of the lipid membrane define the physical properties of the bilayer and consequently affect the function of the incorporated membrane transporters, which also applies for the prominent Ca2+ release-activated Ca2+ ion channel (CRAC). This channel is activated [...] Read more.
The composition and dynamics of the lipid membrane define the physical properties of the bilayer and consequently affect the function of the incorporated membrane transporters, which also applies for the prominent Ca2+ release-activated Ca2+ ion channel (CRAC). This channel is activated by receptor-induced Ca2+ store depletion of the endoplasmic reticulum (ER) and consists of two transmembrane proteins, STIM1 and Orai1. STIM1 is anchored in the ER membrane and senses changes in the ER luminal Ca2+ concentration. Orai1 is the Ca2+-selective, pore-forming CRAC channel component located in the plasma membrane (PM). Ca2+ store-depletion of the ER triggers activation of STIM1 proteins, which subsequently leads to a conformational change and oligomerization of STIM1 and its coupling to as well as activation of Orai1 channels at the ER-PM contact sites. Although STIM1 and Orai1 are sufficient for CRAC channel activation, their efficient activation and deactivation is fine-tuned by a variety of lipids and lipid- and/or ER-PM junction-dependent accessory proteins. The underlying mechanisms for lipid-mediated CRAC channel modulation as well as the still open questions, are presented in this review. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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