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Special Issue "Membrane Channels in Human Diseases: The Spanish Ion Channel Initiative Consortium (SICI)"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (14 December 2018).

Special Issue Editors

Prof. Dr. Antonio Ferrer-Montiel
E-Mail Website
Guest Editor
IDiBE, Universitas Miguel Hernández, Edificio Torregaitán, 03202 Elche, Spain
Interests: sensory neurobiology; pathophysiology of pain; TRP channels; pain pharmacology; drug discovery
Special Issues and Collections in MDPI journals
Prof. Dr. Antonio Felipe
E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Medicine, Institut de Biomedicina, Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain
Interests: voltage-dependent potassium channels; functional complex; oligomeric association; traffic; lipid rafts; post-translational modifications
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Ion channels are membrane proteins that play crucial roles in all forms of life and are highly conserved from bacteria to humans. Ion channel activity is an important pillar to cellular homeostasis and maintenance of health. Because of their contribution to the pathophysiology of several human maladies, these proteins are targets of many drugs, from antiepileptic to analgesics. In addition, they are also the off-targets of a plethora of molecules. Thus, ion channel dysfunction is at the onset of several human diseases known as channelopathies, as well as the unwanted drug side effects. The establishment of an integrative and pluridisciplinary ion channel research program brings together the complementary skills needed for advancing our current knowledge on the ion channel field, from pathophysiology to drug discovery.

To accomplish this ambitious goal, the Spanish Ion Channel Initiative (SICI), an interinstitutional consortium, was established in Spain. SICI is a Network of Excellence on translational research that embraces all aspects of ion channels from genes to organisms, and from basic research to the clinic. In addition to the foundational SICI members, additional groups have joined this research initiative. This special issue is particularly devoted to members and associated groups of the SICI, but also open to those researching in the ion channel field. Thus, we invite all interested colleagues to contribute either with original research or review articles to this Special Issue aiming to provide a comprehensive overview on the current knowledge about ion channel research.

Prof. Dr. Antonio Ferrer-Montiel
Prof. Dr. Antonio Felipe
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • nerve transmission
  • cardiac action potential
  • non excitable cell physiology
  • cancer and apoptosis
  • structure
  • channelopathies
  • drug discovery
  • molecular physiology
  • molecular architecture
  • genetics

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Published Papers (16 papers)

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Editorial

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Editorial
The Spanish Ion Channel Initiative (SICI) Consortium: Ten Years (2008–2018) of a Network of Excellence on Ion Channel Research
Int. J. Mol. Sci. 2018, 19(11), 3514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113514 - 08 Nov 2018
Viewed by 636
Abstract
The Spanish Ion Channel Initiative consortium (SICI, http://sici. [...] Full article

Research

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Article
Role of GirK Channels in Long-Term Potentiation of Synaptic Inhibition in an In Vivo Mouse Model of Early Amyloid-β Pathology
Int. J. Mol. Sci. 2019, 20(5), 1168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051168 - 07 Mar 2019
Cited by 10 | Viewed by 1370
Abstract
Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer’s disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. [...] Read more.
Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer’s disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. Here, we evaluate the relationship between GirK channel activity and inhibitory hippocampal functionality in vivo. In a non-transgenic mouse model of AD, field postsynaptic potentials (fPSPs) from the CA3–CA1 synapse in the dorsal hippocampus were recorded in freely moving mice. Intracerebroventricular (ICV) injections of amyloid-β (Aβ) or GirK channel modulators impaired ionotropic (GABAA-mediated fPSPs) and metabotropic (GirK-mediated fPSPs) inhibitory signaling and disrupted the potentiation of synaptic inhibition. However, the activation of GirK channels prevented Aβ-induced changes in GABAA components. Our data shows, for the first time, the presence of long-term potentiation (LTP) for both the GABAA and GirK-mediated inhibitory postsynaptic responses in vivo. In addition, our results support the importance of an accurate level of GirK-dependent signaling for dorsal hippocampal performance in early amyloid pathology models by controlling the excess of excitation that disrupts synaptic plasticity processes. Full article
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Article
Accessibility of Cations to the Selectivity Filter of KcsA in the Inactivated State: An Equilibrium Binding Study
Int. J. Mol. Sci. 2019, 20(3), 689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030689 - 05 Feb 2019
Cited by 2 | Viewed by 1174
Abstract
Cation binding under equilibrium conditions has been used as a tool to explore the accessibility of permeant and nonpermeant cations to the selectivity filter in three different inactivated models of the potassium channel KcsA. The results show that the stack of ion binding [...] Read more.
Cation binding under equilibrium conditions has been used as a tool to explore the accessibility of permeant and nonpermeant cations to the selectivity filter in three different inactivated models of the potassium channel KcsA. The results show that the stack of ion binding sites (S1 to S4) in the inactivated filter models remain accessible to cations as they are in the resting channel state. The inactivated state of the selectivity filter is therefore “resting-like” under such equilibrium conditions. Nonetheless, quantitative differences in the apparent KD’s of the binding processes reveal that the affinity for the binding of permeant cations to the inactivated channel models, mainly K+, decreases considerably with respect to the resting channel. This is likely to cause a loss of K+ from the inactivated filter and consequently, to promote nonconductive conformations. The most affected site by the affinity loss seems to be S4, which is interesting because S4 is the first site to accommodate K+ coming from the channel vestibule when K+ exits the cell. Moreover, binding of the nonpermeant species, Na+, is not substantially affected by inactivation, meaning that the inactivated channels are also less selective for permeant versus nonpermeant cations under equilibrium conditions. Full article
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Communication
The Membrane Proximal Domain of TRPV1 and TRPV2 Channels Mediates Protein–Protein Interactions and Lipid Binding In Vitro
Int. J. Mol. Sci. 2019, 20(3), 682; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030682 - 05 Feb 2019
Cited by 1 | Viewed by 1449
Abstract
Constitutive or regulated membrane protein trafficking is a key cell biology process. Transient receptor potential channels are somatosensory proteins in charge of detecting several physical and chemical stimuli, thus requiring fine vesicular trafficking. The membrane proximal or pre-S1 domain (MPD) is a highly [...] Read more.
Constitutive or regulated membrane protein trafficking is a key cell biology process. Transient receptor potential channels are somatosensory proteins in charge of detecting several physical and chemical stimuli, thus requiring fine vesicular trafficking. The membrane proximal or pre-S1 domain (MPD) is a highly conserved domain in transient receptor potential channels from the vanilloid (TRPV) subfamily. MPD shows traits corresponding to protein-protein and lipid-protein interactions, and protein regulatory regions. We have expressed MPD of TRPV1 and TRPV2 as green fluorescente protein (GFP)-fusion proteins to perform an in vitro biochemical and biophysical characterization. Pull-down experiments indicate that MPD recognizes and binds Soluble N-ethylmaleimide-sensitive factor Attachment Protein Receptors (SNARE). Synchrotron radiation scattering experiments show that this domain does not self-oligomerize. MPD interacts with phosphatidic acid (PA), a metabolite of the phospholipase D (PLD) pathway, in a specific manner as shown by lipid strips and Trp fluorescence quenching experiments. We show for the first time, to the best of our knowledge, the binding to PA of an N-terminus domain in TRPV channels. The presence of a PA binding domain in TRPV channels argues for putative PLD regulation. Findings in this study open new perspectives to understand the regulated and constitutive trafficking of TRPV channels exerted by protein-protein and lipid-protein interactions. Full article
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Article
Lipid Headgroup Charge and Acyl Chain Composition Modulate Closure of Bacterial β-Barrel Channels
Int. J. Mol. Sci. 2019, 20(3), 674; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030674 - 05 Feb 2019
Cited by 5 | Viewed by 1404
Abstract
The outer membrane of Gram-negative bacteria contains β-barrel proteins that form high-conducting ion channels providing a path for hydrophilic molecules, including antibiotics. Traditionally, these proteins have been considered to exist only in an open state so that regulation of outer membrane permeability was [...] Read more.
The outer membrane of Gram-negative bacteria contains β-barrel proteins that form high-conducting ion channels providing a path for hydrophilic molecules, including antibiotics. Traditionally, these proteins have been considered to exist only in an open state so that regulation of outer membrane permeability was accomplished via protein expression. However, electrophysiological recordings show that β-barrel channels respond to transmembrane voltages by characteristically switching from a high-conducting, open state, to a so-called ‘closed’ state, with reduced permeability and possibly exclusion of large metabolites. Here, we use the bacterial porin OmpF from E. coli as a model system to gain insight on the control of outer membrane permeability by bacterial porins through the modulation of their open state. Using planar bilayer electrophysiology, we perform an extensive study of the role of membrane lipids in the OmpF channel closure by voltage. We pay attention not only to the effects of charges in the hydrophilic lipid heads but also to the contribution of the hydrophobic tails in the lipid-protein interactions. Our results show that gating kinetics is governed by lipid characteristics so that each stage of a sequential closure is different from the previous one, probably because of intra- or intermonomeric rearrangements. Full article
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Article
Expression, Cellular and Subcellular Localisation of Kv4.2 and Kv4.3 Channels in the Rodent Hippocampus
Int. J. Mol. Sci. 2019, 20(2), 246; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020246 - 09 Jan 2019
Cited by 13 | Viewed by 1637
Abstract
The Kv4 family of voltage-gated K+ channels underlie the fast transient (A-type) outward K+ current. Although A-type currents are critical to determine somato-dendritic integration in central neurons, relatively little is known about the precise subcellular localisation of the underlying channels in [...] Read more.
The Kv4 family of voltage-gated K+ channels underlie the fast transient (A-type) outward K+ current. Although A-type currents are critical to determine somato-dendritic integration in central neurons, relatively little is known about the precise subcellular localisation of the underlying channels in hippocampal circuits. Using histoblot and immunoelectron microscopic techniques, we investigated the expression, regional distribution and subcellular localisation of Kv4.2 and Kv4.3 in the adult brain, as well as the ontogeny of their expression during postnatal development. Histoblot demonstrated that Kv4.2 and Kv4.3 proteins were widely expressed in the brain, with mostly non-overlapping patterns. During development, levels of Kv4.2 and Kv4.3 increased with age but showed marked region- and developmental stage-specific differences. Immunoelectron microscopy showed that labelling for Kv4.2 and Kv4.3 was differentially present in somato-dendritic domains of hippocampal principal cells and interneurons, including the synaptic specialisation. Quantitative analyses indicated that most immunoparticles for Kv4.2 and Kv4.3 were associated with the plasma membrane in dendritic spines and shafts, and that the two channels showed very similar distribution patterns in spines of principal cells and along the surface of granule cells. Our data shed new light on the subcellular localisation of Kv4 channels and provide evidence for their non-uniform distribution over the plasma membrane of hippocampal neurons. Full article
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Article
Overexpression of P2X3 and P2X7 Receptors and TRPV1 Channels in Adrenomedullary Chromaffin Cells in a Rat Model of Neuropathic Pain
Int. J. Mol. Sci. 2019, 20(1), 155; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010155 - 03 Jan 2019
Cited by 16 | Viewed by 1940
Abstract
We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury [...] Read more.
We have tested the hypothesis that neuropathic pain acting as a stressor drives functional plasticity in the sympathoadrenal system. The relation between neuropathic pain and adrenal medulla function was studied with behavioral, immunohistochemical and electrophysiological techniques in rats subjected to chronic constriction injury of the sciatic nerve. In slices of the adrenal gland from neuropathic animals, we have evidenced increased cholinergic innervation and spontaneous synaptic activity at the splanchnic nerve–chromaffin cell junction. Likewise, adrenomedullary chromaffin cells displayed enlarged acetylcholine-evoked currents with greater sensitivity to α-conotoxin RgIA, a selective blocker of α9 subunit-containing nicotinic acetylcholine receptors, as well as increased exocytosis triggered by voltage-activated Ca2+ entry. Altogether, these adaptations are expected to facilitate catecholamine output into the bloodstream. Last, but most intriguing, functional and immunohistochemical data indicate that P2X3 and P2X7 purinergic receptors and transient receptor potential vanilloid-1 (TRPV1) channels are overexpressed in chromaffin cells from neuropathic animals. These latter observations are reminiscent of molecular changes characteristic of peripheral sensitization of nociceptors following the lesion of a peripheral nerve, and suggest that similar phenomena can occur in other tissues, potentially contributing to behavioral manifestations of neuropathic pain. Full article
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Review

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Review
Ion Channels and Thermosensitivity: TRP, TREK, or Both?
Int. J. Mol. Sci. 2019, 20(10), 2371; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102371 - 14 May 2019
Cited by 15 | Viewed by 2081
Abstract
Controlling body temperature is a matter of life or death for most animals, and in mammals the complex thermoregulatory system is comprised of thermoreceptors, thermosensors, and effectors. The activity of thermoreceptors and thermoeffectors has been studied for many years, yet only recently have [...] Read more.
Controlling body temperature is a matter of life or death for most animals, and in mammals the complex thermoregulatory system is comprised of thermoreceptors, thermosensors, and effectors. The activity of thermoreceptors and thermoeffectors has been studied for many years, yet only recently have we begun to obtain a clear picture of the thermosensors and the molecular mechanisms involved in thermosensory reception. An important step in this direction was the discovery of the thermosensitive transient receptor potential (TRP) cationic channels, some of which are activated by increases in temperature and others by a drop in temperature, potentially converting the cells in which they are expressed into heat and cold receptors. More recently, the TWIK-related potassium (TREK) channels were seen to be strongly activated by increases in temperature. Hence, in this review we want to assess the hypothesis that both these groups of channels can collaborate, possibly along with other channels, to generate the wide range of thermal sensations that the nervous system is capable of handling. Full article
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Review
Experimental Models of Brugada syndrome
Int. J. Mol. Sci. 2019, 20(9), 2123; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092123 - 29 Apr 2019
Cited by 9 | Viewed by 2015
Abstract
Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise [...] Read more.
Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date. Full article
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Review
Current Structural Knowledge on the CNNM Family of Magnesium Transport Mediators
Int. J. Mol. Sci. 2019, 20(5), 1135; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051135 - 06 Mar 2019
Cited by 11 | Viewed by 1663
Abstract
The cyclin and cystathionine β-synthase (CBS) domain magnesium transport mediators, CNNMs, are key players in maintaining the homeostasis of magnesium in different organs. The human family includes four members, whose impaired activity causes diseases such as Jalili Syndrome or Familial Hypomagnesemia, but is [...] Read more.
The cyclin and cystathionine β-synthase (CBS) domain magnesium transport mediators, CNNMs, are key players in maintaining the homeostasis of magnesium in different organs. The human family includes four members, whose impaired activity causes diseases such as Jalili Syndrome or Familial Hypomagnesemia, but is also linked to neuropathologic disorders, altered blood pressure, and infertility. Recent findings demonstrated that CNNMs are associated with the highly oncogenic phosphatases of the regenerating liver to promote tumor growth and metastasis, which has attracted renewed focus on their potential exploitation as targets for cancer treatment. However, the exact function of CNNMs remains unclear and is subject to debate, proposed as either direct transporters, sensors, or homeostatic factors. This review gathers the current structural knowledge on the CNNM family, highlighting similarities and differences with the closely related structural partners such as the bacterial Mg2+/Co2+ efflux protein CorC and the Mg2+ channel MgtE. Full article
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Review
Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease
Int. J. Mol. Sci. 2019, 20(5), 1034; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051034 - 27 Feb 2019
Cited by 8 | Viewed by 1937
Abstract
Astrocytes are the most abundant cell type in the CNS (central nervous system). They exert multiple functions during development and in the adult CNS that are essential for brain homeostasis. Both cation and anion channel activities have been identified in astrocytes and it [...] Read more.
Astrocytes are the most abundant cell type in the CNS (central nervous system). They exert multiple functions during development and in the adult CNS that are essential for brain homeostasis. Both cation and anion channel activities have been identified in astrocytes and it is believed that they play key roles in astrocyte function. Whereas the proteins and the physiological roles assigned to cation channels are becoming very clear, the study of astrocytic chloride channels is in its early stages. In recent years, we have moved from the identification of chloride channel activities present in astrocyte primary culture to the identification of the proteins involved in these activities, the determination of their 3D structure and attempts to gain insights about their physiological role. Here, we review the recent findings related to the main chloride channels identified in astrocytes: the voltage-dependent ClC-2, the calcium-activated bestrophin, the volume-activated VRAC (volume-regulated anion channel) and the stress-activated Maxi-Cl. We discuss key aspects of channel biophysics and structure with a focus on their role in glial physiology and human disease. Full article
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Review
The Potassium Channel Odyssey: Mechanisms of Traffic and Membrane Arrangement
Int. J. Mol. Sci. 2019, 20(3), 734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030734 - 09 Feb 2019
Cited by 15 | Viewed by 1691
Abstract
Ion channels are transmembrane proteins that conduct specific ions across biological membranes. Ion channels are present at the onset of many cellular processes, and their malfunction triggers severe pathologies. Potassium channels (KChs) share a highly conserved signature that is necessary to conduct K [...] Read more.
Ion channels are transmembrane proteins that conduct specific ions across biological membranes. Ion channels are present at the onset of many cellular processes, and their malfunction triggers severe pathologies. Potassium channels (KChs) share a highly conserved signature that is necessary to conduct K+ through the pore region. To be functional, KChs require an exquisite regulation of their subcellular location and abundance. A wide repertoire of signatures facilitates the proper targeting of the channel, fine-tuning the balance that determines traffic and location. These signature motifs can be part of the secondary or tertiary structure of the protein and are spread throughout the entire sequence. Furthermore, the association of the pore-forming subunits with different ancillary proteins forms functional complexes. These partners can modulate traffic and activity by adding their own signatures as well as by exposing or masking the existing ones. Post-translational modifications (PTMs) add a further dimension to traffic regulation. Therefore, the fate of a KCh is not fully dependent on a gene sequence but on the balance of many other factors regulating traffic. In this review, we assemble recent evidence contributing to our understanding of the spatial expression of KChs in mammalian cells. We compile specific signatures, PTMs, and associations that govern the destination of a functional channel. Full article
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Review
The Crossroad of Ion Channels and Calmodulin in Disease
Int. J. Mol. Sci. 2019, 20(2), 400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020400 - 18 Jan 2019
Cited by 12 | Viewed by 1623
Abstract
Calmodulin (CaM) is the principal Ca2+ sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes that encode identical CaM proteins lead to major cardiac dysfunction, revealing the importance in the regulation [...] Read more.
Calmodulin (CaM) is the principal Ca2+ sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes that encode identical CaM proteins lead to major cardiac dysfunction, revealing the importance in the regulation of excitability. In turn, some mutations at the CaM binding site of ion channels cause similar diseases. Here we provide a summary of the two sides of the partnership between CaM and ion channels, describing the diversity of consequences of mutations at the complementary CaM binding domains. Full article
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Review
TRP Channels as Sensors of Chemically-Induced Changes in Cell Membrane Mechanical Properties
Int. J. Mol. Sci. 2019, 20(2), 371; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020371 - 16 Jan 2019
Cited by 16 | Viewed by 2190
Abstract
Transient Receptor Potential ion channels (TRPs) have been described as polymodal sensors, being responsible for transducing a wide variety of stimuli, and being involved in sensory functions such as chemosensation, thermosensation, mechanosensation, and photosensation. Mechanical and chemical stresses exerted on the membrane can [...] Read more.
Transient Receptor Potential ion channels (TRPs) have been described as polymodal sensors, being responsible for transducing a wide variety of stimuli, and being involved in sensory functions such as chemosensation, thermosensation, mechanosensation, and photosensation. Mechanical and chemical stresses exerted on the membrane can be transduced by specialized proteins into meaningful intracellular biochemical signaling, resulting in physiological changes. Of particular interest are compounds that can change the local physical properties of the membrane, thereby affecting nearby proteins, such as TRP channels, which are highly sensitive to the membrane environment. In this review, we provide an overview of the current knowledge of TRP channel activation as a result of changes in the membrane properties induced by amphipathic structural lipidic components such as cholesterol and diacylglycerol, and by exogenous amphipathic bacterial endotoxins. Full article
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Review
New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question
Int. J. Mol. Sci. 2019, 20(2), 248; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020248 - 10 Jan 2019
Cited by 13 | Viewed by 1776
Abstract
Voltage-dependent potassium channels (Kv channels) are crucial regulators of cell excitability that participate in a range of physiological and pathophysiological processes. These channels are molecular machines that display a mechanism (known as gating) for opening and closing a gate located in a pore [...] Read more.
Voltage-dependent potassium channels (Kv channels) are crucial regulators of cell excitability that participate in a range of physiological and pathophysiological processes. These channels are molecular machines that display a mechanism (known as gating) for opening and closing a gate located in a pore domain (PD). In Kv channels, this mechanism is triggered and controlled by changes in the magnitude of the transmembrane voltage sensed by a voltage-sensing domain (VSD). In this review, we consider several aspects of the VSD–PD coupling in Kv channels, and in some relatives, that share a common general structure characterized by a single square-shaped ion conduction pore in the center, surrounded by four VSDs located at the periphery. We compile some recent advances in the knowledge of their architecture, based in cryo-electron microscopy (cryo-EM) data for high-resolution determination of their structure, plus some new functional data obtained with channel variants in which the covalent continuity between the VSD and PD modules has been interrupted. These advances and new data bring about some reconsiderations about the use of exclusively a classical electromechanical lever model of VSD–PD coupling by some Kv channels, and open a view of the Kv-type channels as allosteric machines in which gating may be dynamically influenced by some long-range interactional/allosteric mechanisms. Full article
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Review
Store-Operated Ca2+ Entry in Breast Cancer Cells: Remodeling and Functional Role
Int. J. Mol. Sci. 2018, 19(12), 4053; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124053 - 14 Dec 2018
Cited by 19 | Viewed by 1532
Abstract
Breast cancer is the most common type of cancer in women. It is a heterogeneous disease that ranges from the less undifferentiated luminal A to the more aggressive basal or triple negative breast cancer molecular subtype. Ca2+ influx from the extracellular medium, [...] Read more.
Breast cancer is the most common type of cancer in women. It is a heterogeneous disease that ranges from the less undifferentiated luminal A to the more aggressive basal or triple negative breast cancer molecular subtype. Ca2+ influx from the extracellular medium, but more specifically store-operated Ca2+ entry (SOCE), has been reported to play an important role in tumorigenesis and the maintenance of a variety of cancer hallmarks, including cell migration, proliferation, invasion or epithelial to mesenchymal transition. Breast cancer cells remodel the expression and functional role of the molecular components of SOCE. This review focuses on the functional role and remodeling of SOCE in breast cancer cells. The current studies suggest the need to deepen our understanding of SOCE in the biology of the different breast cancer subtypes in order to develop new and specific therapeutic strategies. Full article
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