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Membrane Channels in Health and Diseases
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Membrane Channels in Health and Diseases

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 (31 March 2021) | Viewed by 49391

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, Collections and Topics 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, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ion channels are integral membrane proteins that play essential physiological roles. These specialized membrane proteins are responsible for the ions fluxes across the plasma membrane of all mammalian cells. Channels form functional oligomeric complexes by association with ancillary proteins, contributing to the cellular homeostasis and maintenance of health. Numerous cellular events control and are controlled by channel gating and kinetics. Membrane channels, with different ion selectivity, regulate membrane potential and excitability, shape the action potential, and elicit muscle contraction, among other cellular processes. Due to their contribution to the pathophysiology of various human diseases, these proteins are targets of many drugs, from antiepileptics to analgesics. Therefore, ion channel dysfunction at the onset of several human ailments are known as channelopathies, which include autoimmune, metabolic, neural, and cardiovascular diseases. The responsible abnormal behavior can be triggered by an altered function, impaired cell biology, genetic alterations, or drug-acquired response, among other events.

This Special Issue will assemble a series of reviews and research articles updating the state of knowledge on membrane channels in health and diseases. These contributions will inform of new progresses in the field and provide new therapeutic approaches for ion-channel-related diseases. This Special Issue is the second and renovated edition of the first Special Issue, “Membrane Channels in Human Diseases”, launched in 2018, which has been successful in terms of global visibility and acceptance.

Prof. Dr. Antonio Ferrer-Montiel
Prof. Dr. Antonio Felipe
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. 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
  • bacterial physiology and infection
  • virus infection
  • plants physiology
  • toxins

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Published Papers (18 papers)

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Editorial

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2 pages, 170 KiB  
Editorial
Membrane Channels in Health and Diseases
by Antonio Felipe and Antonio Ferrer-Montiel
Int. J. Mol. Sci. 2023, 24(7), 6719; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076719 - 04 Apr 2023
Viewed by 750
Abstract
The goal of this Special Issue, entitled “Membrane Channels in Health and Diseases (https://www [...] Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)

Research

Jump to: Editorial, Review

22 pages, 4036 KiB  
Article
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity
by María Ángeles Bonache, Pedro Juan Llabrés, Cristina Martín-Escura, Roberto De la Torre-Martínez, Alicia Medina-Peris, Laura Butrón, Isabel Gómez-Monterrey, Ana María Roa, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel, Asia Fernández-Carvajal and Rosario González-Muñiz
Int. J. Mol. Sci. 2021, 22(5), 2370; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052370 - 27 Feb 2021
Cited by 3 | Viewed by 2677
Abstract
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, [...] Read more.
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3′-phenyl-2′-dibenzylamino)prop-1′-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2′R > 3S,4S,2′R ≅ 3R,4R,2′S > 3S,4S,2′S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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12 pages, 2243 KiB  
Article
KV1.5–KVβ1.3 Recycling Is PKC-Dependent
by Alvaro Macias, Alicia de la Cruz, Diego A. Peraza, Angela de Benito-Bueno, Teresa Gonzalez and Carmen Valenzuela
Int. J. Mol. Sci. 2021, 22(3), 1336; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031336 - 29 Jan 2021
Cited by 2 | Viewed by 1967
Abstract
KV1.5 channel function is modified by different regulatory subunits. KVβ1.3 subunits assemble with KV1.5 channels and induce a fast and incomplete inactivation. Inhibition of PKC abolishes the KVβ1.3-induced fast inactivation, decreases the amplitude of the [...] Read more.
KV1.5 channel function is modified by different regulatory subunits. KVβ1.3 subunits assemble with KV1.5 channels and induce a fast and incomplete inactivation. Inhibition of PKC abolishes the KVβ1.3-induced fast inactivation, decreases the amplitude of the current KV1.5–KVβ1.3 and modifies their pharmacology likely due to changes in the traffic of KV1.5–KVβ1.3 channels in a PKC-dependent manner. In order to analyze this hypothesis, HEK293 cells were transfected with KV1.5–KVβ1.3 channels, and currents were recorded by whole-cell configuration of the patch-clamp technique. The presence of KV1.5 in the membrane was analyzed by biotinylation techniques, live cell imaging and confocal microscopy approaches. PKC inhibition resulted in a decrease of 33 ± 7% of channels in the cell surface due to reduced recycling to the plasma membrane, as was confirmed by confocal microscopy. Live cell imaging indicated that PKC inhibition almost abolished the recycling of the KV1.5–KVβ1.3 channels, generating an accumulation of channels into the cytoplasm. All these results suggest that the trafficking regulation of KV1.5–KVβ1.3 channels is dependent on phosphorylation by PKC and, therefore, they could represent a clinically relevant issue, mainly in those diseases that exhibit modifications in PKC activity. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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17 pages, 7088 KiB  
Article
Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators
by Marta Ximenis, José Mulet, Salvador Sala, Francisco Sala, Manuel Criado, Rosario González-Muñiz and María Jesús Pérez de Vega
Int. J. Mol. Sci. 2021, 22(2), 973; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020973 - 19 Jan 2021
Cited by 7 | Viewed by 2896
Abstract
The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained [...] Read more.
The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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19 pages, 2286 KiB  
Article
Application of Machine-Learning Methods to Recognize mitoBK Channels from Different Cell Types Based on the Experimental Patch-Clamp Results
by Monika Richter-Laskowska, Paulina Trybek, Piotr Bednarczyk and Agata Wawrzkiewicz-Jałowiecka
Int. J. Mol. Sci. 2021, 22(2), 840; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020840 - 15 Jan 2021
Cited by 4 | Viewed by 1957
Abstract
(1) Background: In this work, we focus on the activity of large-conductance voltage- and Ca2+-activated potassium channels (BK) from the inner mitochondrial membrane (mitoBK). The characteristic electrophysiological features of the mitoBK channels are relatively high single-channel conductance (ca. 300 pS) [...] Read more.
(1) Background: In this work, we focus on the activity of large-conductance voltage- and Ca2+-activated potassium channels (BK) from the inner mitochondrial membrane (mitoBK). The characteristic electrophysiological features of the mitoBK channels are relatively high single-channel conductance (ca. 300 pS) and types of activating and deactivating stimuli. Nevertheless, depending on the isoformal composition of mitoBK channels in a given membrane patch and the type of auxiliary regulatory subunits (which can be co-assembled to the mitoBK channel protein) the characteristics of conformational dynamics of the channel protein can be altered. Consequently, the individual features of experimental series describing single-channel activity obtained by patch-clamp method can also vary. (2) Methods: Artificial intelligence approaches (deep learning) were used to classify the patch-clamp outputs of mitoBK activity from different cell types. (3) Results: Application of the K-nearest neighbors algorithm (KNN) and the autoencoder neural network allowed to perform the classification of the electrophysiological signals with a very good accuracy, which indicates that the conformational dynamics of the analyzed mitoBK channels from different cell types significantly differs. (4) Conclusion: We displayed the utility of machine-learning methodology in the research of ion channel gating, even in cases when the behavior of very similar microbiosystems is analyzed. A short excerpt from the patch-clamp recording can serve as a “fingerprint” used to recognize the mitoBK gating dynamics in the patches of membrane from different cell types. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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14 pages, 5614 KiB  
Article
Optogenetic Modulation of Neural Progenitor Cells Improves Neuroregenerative Potential
by Esther Giraldo, David Palmero-Canton, Beatriz Martinez-Rojas, Maria del Mar Sanchez-Martin and Victoria Moreno-Manzano
Int. J. Mol. Sci. 2021, 22(1), 365; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010365 - 31 Dec 2020
Cited by 8 | Viewed by 3605
Abstract
Neural progenitor cell (NPC) transplantation possesses enormous potential for the treatment of disorders and injuries of the central nervous system, including the replacement of lost cells or the repair of host neural circuity after spinal cord injury (SCI). Importantly, cell-based therapies in this [...] Read more.
Neural progenitor cell (NPC) transplantation possesses enormous potential for the treatment of disorders and injuries of the central nervous system, including the replacement of lost cells or the repair of host neural circuity after spinal cord injury (SCI). Importantly, cell-based therapies in this context still require improvements such as increased cell survival and host circuit integration, and we propose the implementation of optogenetics as a solution. Blue-light stimulation of NPCs engineered to ectopically express the excitatory light-sensitive protein channelrhodopsin-2 (ChR2-NPCs) prompted an influx of cations and a subsequent increase in proliferation and differentiation into oligodendrocytes and neurons and the polarization of astrocytes from a pro-inflammatory phenotype to a pro-regenerative/anti-inflammatory phenotype. Moreover, neurons derived from blue-light-stimulated ChR2-NPCs exhibited both increased branching and axon length and improved axon growth in the presence of axonal inhibitory drugs such as lysophosphatidic acid or chondroitin sulfate proteoglycan. Our results highlight the enormous potential of optogenetically stimulated NPCs as a means to increase neuroregeneration and improve cell therapy outcomes for enhancing better engraftments and cell identity upon transplantation in conditions such as SCI. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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16 pages, 2100 KiB  
Article
The Adrenal Medulla Modulates Mechanical Allodynia in a Rat Model of Neuropathic Pain
by Marina Arribas-Blázquez, Luis Alcides Olivos-Oré, María Victoria Barahona, Aneta Wojnicz, Ricardo De Pascual, Mercedes Sánchez de la Muela, Antonio G. García and Antonio R. Artalejo
Int. J. Mol. Sci. 2020, 21(21), 8325; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218325 - 06 Nov 2020
Cited by 2 | Viewed by 1906
Abstract
We have investigated whether the stress response mediated by the adrenal medulla in rats subjected to chronic constriction injury of the sciatic nerve (CCI) modulates their nocifensive behavior. Treatment with SK29661 (300 mg/kg; intraperitoneal (I.P.)), a selective inhibitor of phenylethanolamine N-methyltransferase (PNMT) that [...] Read more.
We have investigated whether the stress response mediated by the adrenal medulla in rats subjected to chronic constriction injury of the sciatic nerve (CCI) modulates their nocifensive behavior. Treatment with SK29661 (300 mg/kg; intraperitoneal (I.P.)), a selective inhibitor of phenylethanolamine N-methyltransferase (PNMT) that converts noradrenaline (NA) into adrenaline (A), fully reverted mechanical allodynia in the injured hind paw without affecting mechanical sensitivity in the contralateral paw. The effect was fast and reversible and was associated with a decrease in the A to NA ratio (A/NA) in the adrenal gland and circulating blood, an A/NA that was elevated by CCI. 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (SKF29661) did not affect exocytosis evoked by Ca2+ entry as well as major ionic conductances (voltage-gated Na+, Ca2+, and K+ channels, nicotinic acetylcholine receptors) involved in stimulus-secretion coupling in chromaffin cells, suggesting that it acted by changing the relative content of the two adrenal catecholamines. Denervation of the adrenal medulla by surgical splanchnectomy attenuated mechanical allodynia in neuropathic animals, hence confirming the involvement of the adrenal medulla in the pathophysiology of the CCI model. Inhibition of PNMT appears to be an effective and probably safe way to modulate adrenal medulla activity and, in turn, to alleviate pain secondary to the injury of a peripheral nerve. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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14 pages, 3046 KiB  
Article
Nicotinic Receptor Subunits Atlas in the Adult Human Lung
by Zania Diabasana, Jeanne-Marie Perotin, Randa Belgacemi, Julien Ancel, Pauline Mulette, Gonzague Delepine, Philippe Gosset, Uwe Maskos, Myriam Polette, Gaëtan Deslée and Valérian Dormoy
Int. J. Mol. Sci. 2020, 21(20), 7446; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207446 - 09 Oct 2020
Cited by 14 | Viewed by 3476
Abstract
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AECs) remains poorly understood, and contribution [...] Read more.
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AECs) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lungs of smokers and non-smokers using transcriptomic data for whole-lung tissues, isolated large AECs, and isolated small AECs. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified an nAChR transcriptomic print at the single-cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChR subunits to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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16 pages, 2050 KiB  
Article
Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification
by Marianna Dionisi, Federico Alessandro Ruffinatti, Beatrice Riva, Dmitry Lim, Annalisa Canta, Cristina Meregalli, Giulia Fumagalli, Laura Monza, Antonio Ferrer-Montiel, Asia Fernandez-Carvajal, Guido Cavaletti, Armando A. Genazzani and Carla Distasi
Int. J. Mol. Sci. 2020, 21(19), 7164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197164 - 28 Sep 2020
Cited by 2 | Viewed by 2408
Abstract
Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic [...] Read more.
Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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20 pages, 3726 KiB  
Article
STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells
by Carlos Pascual-Caro, Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Jaime de Juan-Sanz, Jan B. Parys, Estela Area-Gomez, Eulalia Pozo-Guisado and Francisco Javier Martin-Romero
Int. J. Mol. Sci. 2020, 21(18), 6598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186598 - 09 Sep 2020
Cited by 8 | Viewed by 3371
Abstract
STIM1 is an endoplasmic reticulum (ER) protein that modulates the activity of a number of Ca2+ transport systems. By direct physical interaction with ORAI1, a plasma membrane Ca2+ channel, STIM1 activates the ICRAC current, whereas the binding with the voltage-operated [...] Read more.
STIM1 is an endoplasmic reticulum (ER) protein that modulates the activity of a number of Ca2+ transport systems. By direct physical interaction with ORAI1, a plasma membrane Ca2+ channel, STIM1 activates the ICRAC current, whereas the binding with the voltage-operated Ca2+ channel CaV1.2 inhibits the current through this latter channel. In this way, STIM1 is a key regulator of Ca2+ signaling in excitable and non-excitable cells, and altered STIM1 levels have been reported to underlie several pathologies, including immunodeficiency, neurodegenerative diseases, and cancer. In both sporadic and familial Alzheimer’s disease, a decrease of STIM1 protein levels accounts for the alteration of Ca2+ handling that compromises neuronal cell viability. Using SH-SY5Y cells edited by CRISPR/Cas9 to knockout STIM1 gene expression, this work evaluated the molecular mechanisms underlying the cell death triggered by the deficiency of STIM1, demonstrating that STIM1 is a positive regulator of ITPR3 gene expression. ITPR3 (or IP3R3) is a Ca2+ channel enriched at ER-mitochondria contact sites where it provides Ca2+ for transport into the mitochondria. Thus, STIM1 deficiency leads to a strong reduction of ITPR3 transcript and ITPR3 protein levels, a consequent decrease of the mitochondria free Ca2+ concentration ([Ca2+]mit), reduction of mitochondrial oxygen consumption rate, and decrease in ATP synthesis rate. All these values were normalized by ectopic expression of ITPR3 in STIM1-KO cells, providing strong evidence for a new mode of regulation of [Ca2+]mit mediated by the STIM1-ITPR3 axis. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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19 pages, 9475 KiB  
Article
Cellular and Subcellular Localisation of Kv4-Associated KChIP Proteins in the Rat Cerebellum
by Rocío Alfaro-Ruíz, Carolina Aguado, Alejandro Martín-Belmonte, Ana Esther Moreno-Martínez and Rafael Luján
Int. J. Mol. Sci. 2020, 21(17), 6403; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176403 - 03 Sep 2020
Cited by 6 | Viewed by 2353
Abstract
The K+ channel interacting proteins (KChIPs) are a family of cytosolic proteins that interact with Kv4 channels, leading to higher current density, modulation of channel inactivation and faster recovery from inactivation. Using immunohistochemical techniques at the light and electron microscopic level combined [...] Read more.
The K+ channel interacting proteins (KChIPs) are a family of cytosolic proteins that interact with Kv4 channels, leading to higher current density, modulation of channel inactivation and faster recovery from inactivation. Using immunohistochemical techniques at the light and electron microscopic level combined with quantitative analysis, we investigated the cellular and subcellular localisation of KChIP3 and KChIP4 to compare their distribution patterns with those for Kv4.2 and Kv4.3 in the cerebellar cortex. Immunohistochemistry at the light microscopic level demonstrated that KChIP3, KChIP4, Kv4.2 and Kv4.3 proteins were widely expressed in the cerebellum, with mostly overlapping patterns. Immunoelectron microscopic techniques showed that KChIP3, KChIP4, Kv4.2 and Kv4.3 shared virtually the same somato-dendritic domains of Purkinje cells and granule cells. Application of quantitative approaches showed that KChIP3 and KChIP4 were mainly membrane-associated, but also present at cytoplasmic sites close to the plasma membrane, in dendritic spines and shafts of Purkinje cells (PCs) and dendrites of granule cells (GCs). Similarly, immunoparticles for Kv4.2 and Kv4.3 were observed along the plasma membrane and at intracellular sites in the same neuron populations. In addition to the preferential postsynaptic distribution, KChIPs and Kv4 were also distributed presynaptically in parallel fibres and mossy fibres. Immunoparticles for KChIP3, KChIP4 and Kv4.3 were detected in parallel fibres, and KChIP3, KChIP4, Kv4.2 and Kv4.3 were found in parallel fibres, indicating that composition of KChIP and Kv4 seems to be input-dependent. Together, our findings unravelled previously uncharacterised KChIP and Kv4 subcellular localisation patterns in neurons, revealed that KChIP have additional Kv4-unrelated functions in the cerebellum and support the formation of macromolecular complexes between KChIP3 and KChIP4 with heterotetrameric Kv4.2/Kv4.3 channels. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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13 pages, 2837 KiB  
Article
Remodeling of Kv7.1 and Kv7.5 Expression in Vascular Tumors
by Clara Serrano-Novillo, Anna Oliveras, Joan Carles Ferreres, Enric Condom and Antonio Felipe
Int. J. Mol. Sci. 2020, 21(17), 6019; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176019 - 21 Aug 2020
Cited by 4 | Viewed by 1964
Abstract
Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in [...] Read more.
Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in blood vessels, and they participate in the maintenance of vascular tone and are implicated in myocyte proliferation. Although evidence links Kv7 remodeling to different types of cancer, its expression in vascular tumors has never been studied. Endothelium-derived vascular neoplasms range from indolent lesions to highly aggressive and metastasizing cancers. Here, we show that Kv7.1 and Kv7.5 are evenly distributed in tunicas as well as the endothelium of healthy veins and arteries. The layered structure of vessels is lost in vascular tumors. By studying eight vascular tumors with different origins and characteristics, we found that Kv7.1 and Kv7.5 expression was changed in vascular cancers. While both channels were generally downregulated, Kv7.5 expression was clearly correlated with neoplastic malignancy. The vascular tumors did not contract; therefore, the role of Kv7 channels is probably related to proliferation rather than controlling vascular tone. Our results identify vascular Kv7 channels as targets for cancer detection and anticancer therapies. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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12 pages, 1008 KiB  
Article
Methylmercury Poisoning Induces Cardiac Electrical Remodeling and Increases Arrhythmia Susceptibility and Mortality
by Mara Cristina P. Santos Ruybal, Monica Gallego, Thais Bazoti B. Sottani, Emiliano H. Medei, Oscar Casis and Jose Hamilton M. Nascimento
Int. J. Mol. Sci. 2020, 21(10), 3490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103490 - 15 May 2020
Cited by 4 | Viewed by 2781
Abstract
This study aims to investigate the cardiac electrical remodeling associated with intoxication by methylmercury (MeHg). We evaluated the chronic effects of MeHg on in vivo electrocardiograms and on ex vivo action potentials and depolarizing (ICa-L) and repolarizing (Ito) currents. [...] Read more.
This study aims to investigate the cardiac electrical remodeling associated with intoxication by methylmercury (MeHg). We evaluated the chronic effects of MeHg on in vivo electrocardiograms and on ex vivo action potentials and depolarizing (ICa-L) and repolarizing (Ito) currents. The acute effect of MeHg was evaluated on HEK293 cells expressing human ERG, Kv4.3 and KCNQ1/KCNE1 channels. Chronic MeHg treatment increased QTc and Tpeak–Tend interval duration, prolonged action potential duration and decreased amplitude of Ito and ICa-L. In addition, heterologously expressed IhKv4.3, IhERG or IhKCNQ1/KCNE1 decreased after acute exposure to MeHg at subnanomolar range. The introduction of the in vitro effects of MeHg in a computer model of human ventricular action potentials triggered early afterdepolarizations and arrhythmia. In conclusion, cardiac electrical remodeling induced by MeHg poisoning is related to the reduction of Ito and ICa-L. The acute effect of MeHg on hKv4.3; hERG and hKCNQ1/KCNE1 currents and their transposition to in silico models show an association between MeHg intoxication and acquired Long QT Syndrome in humans. MeHg can exert its high toxicity either after chronic or acute exposure to concentrations as low as picomolar. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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18 pages, 4966 KiB  
Article
Arachidonic Acid Attenuates Cell Proliferation, Migration and Viability by a Mechanism Independent on Calcium Entry
by Carlos Cantonero, Jose Sánchez-Collado, Jose J. Lopez, Ginés M. Salido, Juan A. Rosado and Pedro C. Redondo
Int. J. Mol. Sci. 2020, 21(9), 3315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093315 - 07 May 2020
Cited by 14 | Viewed by 2651
Abstract
Arachidonic acid (AA) is a phospholipase A2 metabolite that has been reported to mediate a plethora of cellular mechanisms involved in healthy and pathological states such as platelet aggregation, lymphocyte activation, and tissue inflammation. AA has been described to activate Ca2+ entry [...] Read more.
Arachidonic acid (AA) is a phospholipase A2 metabolite that has been reported to mediate a plethora of cellular mechanisms involved in healthy and pathological states such as platelet aggregation, lymphocyte activation, and tissue inflammation. AA has been described to activate Ca2+ entry through the arachidonate-regulated Ca2+-selective channels (ARC channels). Here, the analysis of the changes in the intracellular Ca2+ homeostasis revealed that, despite MDA-MB-231 cells expressing the ARC channel components Orai1, Orai3, and STIM1, AA does not evoke Ca2+ entry in these cells. We observed that AA evokes Ca2+ entry in MDA-MB-231 cells transiently expressing ARC channels. Nevertheless, MDA-MB-231 cell treatment with AA reduces cell proliferation and migration while inducing cell death through apoptosis. The latter mostly likely occurs via mitochondria membrane depolarization and the activation of caspases-3, -8, and -9. Altogether, our results indicate that AA exerts anti-tumoral effects on MDA-MB-231 cells, without having any effect on non-tumoral breast epithelial cells, by a mechanism that is independent on the activation of Ca2+ influx via ARC channels. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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Review

Jump to: Editorial, Research

11 pages, 525 KiB  
Review
Contribution of K2P Potassium Channels to Cardiac Physiology and Pathophysiology
by Salvador Herrera-Pérez, Ana Campos-Ríos, Lola Rueda-Ruzafa and José Antonio Lamas
Int. J. Mol. Sci. 2021, 22(12), 6635; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126635 - 21 Jun 2021
Cited by 9 | Viewed by 3450
Abstract
Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later [...] Read more.
Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later detected in cardiac tissue by RT-PCR, although the distribution of the different K2P subfamilies in the heart seems to depend on the species analyzed. In order to collect relevant information in this regard, we focus here on the TWIK, TASK and TREK cardiac channels, their putative roles in cardiac physiology and their implication in coronary pathologies. Most of the RNA expression data and electrophysiological recordings available to date support the presence of these different K2P subfamilies in distinct cardiac cells. Likewise, we show how these channels may be involved in certain pathologies, such as atrial fibrillation, long QT syndrome and Brugada syndrome. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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14 pages, 1029 KiB  
Review
From Channels to Canonical Wnt Signaling: A Pathological Perspective
by Silvia Muccioli, Valentina Brillo, Leonardo Chieregato, Luigi Leanza, Vanessa Checchetto and Roberto Costa
Int. J. Mol. Sci. 2021, 22(9), 4613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094613 - 28 Apr 2021
Cited by 10 | Viewed by 2344
Abstract
Wnt signaling is an important pathway mainly active during embryonic development and controlling cell proliferation. This regulatory pathway is aberrantly activated in several human diseases. Ion channels are known modulators of several important cellular functions ranging from the tuning of the membrane potential [...] Read more.
Wnt signaling is an important pathway mainly active during embryonic development and controlling cell proliferation. This regulatory pathway is aberrantly activated in several human diseases. Ion channels are known modulators of several important cellular functions ranging from the tuning of the membrane potential to modulation of intracellular pathways, in particular the influence of ion channels in Wnt signaling regulation has been widely investigated. This review will discuss the known links between ion channels and canonical Wnt signaling, focusing on their possible roles in human metabolic diseases, neurological disorders, and cancer. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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21 pages, 6841 KiB  
Review
Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs
by Pilar Cercós, Diego A. Peraza, Angela de Benito-Bueno, Paula G. Socuéllamos, Abdoul Aziz-Nignan, Dariel Arrechaga-Estévez, Escarle Beato, Emilio Peña-Acevedo, Armando Albert, Juan A. González-Vera, Yoel Rodríguez, Mercedes Martín-Martínez, Carmen Valenzuela and Marta Gutiérrez-Rodríguez
Int. J. Mol. Sci. 2021, 22(3), 1419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031419 - 31 Jan 2021
Cited by 8 | Viewed by 3813
Abstract
Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on [...] Read more.
Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. KV4.x channels need to assemble with other accessory subunits (β) to fully reproduce the ITO and ISA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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14 pages, 707 KiB  
Review
The Background K+ Channel TRESK in Sensory Physiology and Pain
by Alba Andres-Bilbe, Aida Castellanos, Anna Pujol-Coma, Gerard Callejo, Nuria Comes and Xavier Gasull
Int. J. Mol. Sci. 2020, 21(15), 5206; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155206 - 23 Jul 2020
Cited by 15 | Viewed by 4015
Abstract
TRESK belongs to the K2P family of potassium channels, also known as background or leak potassium channels due to their biophysical properties and their role regulating membrane potential of cells. Several studies to date have highlighted the role of TRESK in regulating [...] Read more.
TRESK belongs to the K2P family of potassium channels, also known as background or leak potassium channels due to their biophysical properties and their role regulating membrane potential of cells. Several studies to date have highlighted the role of TRESK in regulating the excitability of specific subtypes of sensory neurons. These findings suggest TRESK could be involved in pain sensitivity. Here, we review the different evidence available that involves the channel in pain and sensory perception, from studies knocking out the channel or overexpressing it to identified mutations that link the channel to migraine pain. In addition, the therapeutic possibilities are discussed, as targeting the channel seems an interesting therapeutic approach to reduce nociceptor activation and to decrease pain. Full article
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
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