Review
Biochemistry & Molecular Biology
Michela De Bellis, Brigida Boccanegra, Alessandro Giovanni Cerchiara, Paola Imbrici, Annamaria De Luca
Summary: Voltage-gated sodium channels are an important target for drug discovery and are involved in various physiological processes. Blockers of these channels are clinically used in several excitability disorders, including myotonia. However, current treatments are not selective for the specific sodium channel isoform involved in myotonia, highlighting the need for developing more potent and use-dependent drugs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Oscar Brenes, Raffaella Barbieri, Melissa Vasquez, Rebeca Vindas-Smith, Jeffrey Roig, Adarli Romero, Gerardo del Valle, Luis Bermudez-Guzman, Sara Bertelli, Michael Pusch, Fernando Morales
Summary: Non-dystrophic myotonias are associated with loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Na(v)1.4 sodium channel. A family with members diagnosed with Thomsen's disease was found to have novel mutations in CLCN1 and SCN4A genes, leading to myotonia. The study highlights the importance of deep genetic analysis in accurate genetic counseling and patient management.
Article
Biochemistry & Molecular Biology
Chiung-Wei Huang, Pi-Chen Lin, Jian-Lin Chen, Ming-Jen Lee
Summary: The study revealed that CBD selectively binds to the slow-inactivated state of the Na(v)1.4 channel with a higher affinity and faster binding kinetics compared to the fast inactivation state. This differential inhibition of sodium current by CBD suggests its potential therapeutic benefit in treating myotonia resulting from sodium channelopathy.
Review
Biochemistry & Molecular Biology
Oscar Brenes, Michael Pusch, Fernando Morales
Summary: Myotonia congenita is a hereditary muscle disease caused by mutations in the CLCN1 gene, leading to abnormal function of the chloride ion channel and resulting in muscle hyperexcitability and other symptoms. This review examines over 350 reported mutations and analyzes their effects on the structure and function of the chloride ion channel.
Review
Biochemistry & Molecular Biology
Xin Wu, Liang Hong
Summary: Calmodulin (CaM) is a small protein that serves as a ubiquitous signal transducer, regulating neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. Mutations in CaM-binding IQ domain can lead to various diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Marino DiFranco, Stephen C. Cannon
Summary: Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle channelopathy caused by mutations in voltage sensor domains of calcium or sodium channels. Recurrent attacks of weakness are the primary clinical manifestation, resulting from impaired excitability of depolarized fibers containing leaky mutant channels. Reduced Ca2+-release in Ca(V)1.1 mutant channels may contribute to the late-onset permanent muscle weakness in Ca(V)1.1-associated HypoPP. The episodes of transient weakness in both Ca(V)1.1 and Na(V)1.4-associated HypoPP are primarily caused by leaky channels and are not a consequence of reduced Ca2+-release.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Review
Pharmacology & Pharmacy
Sophie Nicole, Philippe Lory
Summary: The Na(v)1.4 sodium channel plays a critical role in skeletal muscle excitability, impacting a spectrum of clinical diseases from muscle stiffness to weakness. Understanding Na(v)1.4 LoF has introduced new therapeutic challenges in improving muscle force.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Neurosciences
Mohamed A. Fouda, Mohammad-Reza Ghovanloo, Peter C. Ruben
Summary: Acquired and inherited dysfunction in voltage-gated sodium channels is the underlying cause of various diseases. Late sodium current increase is a common defect in these diseases.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Genetics & Heredity
Nurul Huda Musa, Karuppiah Thilakavathy, Nur Afiqah Mohamad, Marina L. Kennerson, Liyana Najwa Inche Mat, Wei Chao Loh, Anna Misyail Abdul Rashid, Janudin Baharin, Azliza Ibrahim, Wan Aliaa Wan Sulaiman, Fan Kee Hoo, Hamidon Basri, Abdul Hanif Khan Yusof Khan
Summary: This article reports the first case of Myotonia congenita (MC) in Malaysia, a rare neuromuscular disease caused by mutations in the CLCN1 gene. The patient presented with muscle stiffness and cramp episodes since childhood, and was diagnosed with MC based on electromyography and genetic analysis. Her brother also had similar symptoms.
FRONTIERS IN GENETICS
(2023)
Article
Genetics & Heredity
Kevin Jehasse, Kathleen Jacquerie, Alice de Froidmont, Camille Lemoine, Thierry Grisar, Katrien Stouffs, Bernard Lakaye, Vincent Seutin
Summary: This study identified a novel missense variant in the CLCN1 gene of a patient with myotonia congenita, and demonstrated its effect on channel properties through functional analysis. The variant led to a reduced conductance at resting potential and an overall weakened voltage dependence in the mutant channels.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Lei Zhang, Xueqi Wang, Jingxin Chen, Shaohu Sheng, Thomas R. Kleyman
Summary: Using crosslinking and voltage clamp techniques, we identified specific intersubunit contacts in ENaC that modulate channel activity. Crosslinking between specific residues in the palm and thumb domains of different subunits activated or inhibited ENaC activity. These findings suggest the presence of microswitches at specific subunit interfaces that play a role in ENaC gating and regulation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Jennifer C. Wong, Kameryn M. Butler, Lindsey Shapiro, Jacquelyn T. Thelin, Kari A. Mattison, Kathryn B. Garber, Paula C. Goldenberg, Shobana Kubendran, G. Bradley Schaefer, Andrew Escayg
Summary: SCN8A mutations, mainly de novo missense variants, are associated with epileptic encephalopathy. Mouse models with overlapping in-frame deletions in the voltage sensor region of domain 4 exhibit increased seizure susceptibility. Clinical relevance of mutations is highlighted by identification of patients with the same SCN8A deletion.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Alessandro Farinato, Maria Maddalena Cavalluzzi, Concetta Altamura, Carmen Campanale, Paola Laghetti, Ilaria Saltarella, Pietro Delre, Arthur Barbault, Nancy Tarantino, Gualtiero Milani, Natalie Paola Rotondo, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Sabata Pierno, Giuseppe Felice Mangiatordi, Giovanni Lentini, Jean-Francois Desaphy
Summary: Several commercially available and newly synthesized riluzole analogs were tested as voltage-gated skeletal muscle sodium-channel blockers in vitro. The data obtained from patch-clamp technique showed that potency is correlated with lipophilicity and the presence of a protonatable amino function at the 2-position of benzothiazole enhances the use-dependent behavior of the analogs. The 2-piperazine analog of riluzole (14) demonstrated greater use-dependent Nav1.4 blocking activity despite being slightly less potent than the parent compound in both patch-clamp assay and in vitro myotonia model. Docking studies revealed the key interactions between compound 14 and the amino acids of the local anesthetic binding site within the channel pore. These findings contribute to the discovery of novel compounds for the treatment of cell excitability disorders.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Medicine, Research & Experimental
Kerem Terali, Ayberk Turkyilmaz, Safiye Gunes Sager, Alper Han Cebi
Summary: The study aims to expand the cohort of Turkish patients with SCN1A-positive genetic epilepsy disorders and predict the molecular phenotypes of detected SCN1A variants. Understanding NaV1.1 dysfunction can facilitate the development of targeted therapies and improve clinical outcomes in epilepsy treatment.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2023)
Article
Endocrinology & Metabolism
Alexandra Efthymiadou, Ivan Gautschi, Miguel Xavier van Bemmelen, Amalia Sertedaki, Aristeidis Giannakopoulos, George Chrousos, Laurent Schild, Dionisios Chrysis
Summary: This study investigates the genetic cause of a mild and transient form of pseudohypoaldosteronism type 1 (PHA1). It is found that all 12 patients with PHA1 carry a homozygous missense mutation p.Phe226Cys in the a subunit of ENaC, which leads to a reduction in ENaC activity and explains the symptoms in these patients.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2023)
Article
Cardiac & Cardiovascular Systems
Sarah H. Vermij, Jean-Sebastien Rougier, Esperanza Agullo-Pascual, Eli Rothenberg, Mario Delmar, Hugues Abriel
CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY
(2020)
Article
Physiology
Yaopeng Hu, Daniela Ross Kaschitza, Maria Essers, Prakash Arullampalam, Takayuki Fujita, Hugues Abriel, Ryuji Inoue
Summary: This study reveals the potential arrhythmogenicity of CaMKII-mediated TRPM4 channel overactivation linked to Ca2+ dysregulation in the heart, demonstrating the functional interaction between TRPM4 and CaMKII proteins. Enhanced by angiotensin II treatment, this novel arrhythmic mechanism involving excessive CaMKII activity causing TRPM4 overactivation in the stressed heart was further confirmed through experimental and numerical simulations.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Lijo Cherian Ozhathil, Jean-Sebastien Rougier, Prakash Arullampalam, Maria C. Essers, Daniela Ross-Kaschitza, Hugues Abriel
Summary: Deleting TRPM4 gene in mice results in a reduction in Na+ current in cardiac myocytes, leading to increased sensitivity to Na+ channel blockers and slower intraventricular conduction. This study indicates a novel function of TRPM4 in regulating Na+ current in murine cardiac myocytes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Prakash Arullampalam, Barbara Preti, Daniela Ross-Kaschitza, Martin Lochner, Jean-Sebastien Rougier, Hugues Abriel
Summary: The study reveals species-dependent differences in the response of TRPM4 inhibitors on human and mouse TRPM4 channels. While CBA and NBA can effectively inhibit human TRPM4, they may have different effects on mouse TRPM4. Furthermore, the application of 9-phenanthrol may lead to opposite outcomes for mouse TRPM4 depending on the site of application.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Surgery
Pauline Salamin, Celine Deslarzes-Dubuis, Alban Longchamp, Severine Petitprez, Jean-Pierre Venetz, Jean-Marc Corpataux, Sebastien Deglise
Summary: This study analyzed surgical complications after kidney transplantation and identified potential risk factors. The results showed that complications were frequent, with age, deceased donor, and operative time being identified as risk factors. Vascular complications were the main cause of early graft loss.
ANNALS OF VASCULAR SURGERY
(2022)
Article
Neurosciences
Lolita Dokshokova, Mauro Franzoso, Anna Di Bona, Nicola Moro, Jose Luis Sanchez Alonso, Valentina Prando, Michele Sandre, Cristina Basso, Giuseppe Faggian, Hugues Abriel, Oriano Marin, Julia Gorelik, Tania Zaglia, Marco Mongillo
Summary: Cardiomyocytes release nerve growth factor (NGF) to support innervating sympathetic neurons in the heart, with neuro-cardiac junctions (NCJ) playing a crucial role in supporting retrograde neurotrophic signaling. The direct link between sympathetic neuron survival and neurotrophin release by cardiomyocytes is essential for heart cellular homeostasis.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Medicine, General & Internal
Sebastien Michel Vedani, Severine Petitprez, Eva Weinz, Jean-Marc Corpataux, Sebastien Deglise, Celine Deslarzes-Dubuis, Elisabeth Cote, Jean-Baptiste Ricco, Francois Saucy
Summary: This study found that shrinkage of the aneurysm sac is not significantly associated with improved survival rates or reduced risk of secondary interventions. Regardless of shrinkage, the risk of secondary interventions seems to be more closely linked to compliance with the instructions for use.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Barbara Preti, Jean-Sebastie Rougier, Irida Papapostolou, Florian Bochen, Christian E. Gerber, Hugues Abriel, Martin Lochner, Christine Peinelt
Summary: This study identified TRPM4 inhibitors and investigated the pathophysiology of TRPM4 in cardiac conditions, immune diseases, and cancer using these inhibitors, molecular biology techniques, and functional assays.
Article
Chemistry, Multidisciplinary
Valentina Rossetti, Hugues Abriel
Summary: Funded by the Swiss National Science Foundation and the University of Bern, NCCR TransCure was active from 2010 to 2022, providing a unique research and educational framework in the membrane transporter and ion channel field. Through an interdisciplinary approach and a rich offering in complementary areas, the network achieved outstanding scientific results and contributed to the education of young scientists.
Article
Cardiac & Cardiovascular Systems
Mey Boukenna, Jean-Sebastien Rougier, Parisa Aghagolzadeh, Sylvain Pradervand, Sabrina Guichard, Anne-Flore Hammerli, Thierry Pedrazzini, Hugues Abriel
Summary: TRPM4 plays a critical role in the inflammatory response, cardiac function, and healing after myocardial infarction (MI). Deletion of Trpm4 leads to increased inflammation, fibrosis, and angiogenesis post-MI, which have important implications for the treatment of MI.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2023)
Article
Neurosciences
Zoja Selimi, Jean-Sebastien Rougier, Hugues Abriel, Jan P. P. Kucera
Summary: Cardiac voltage-gated sodium (Na+) channels play a crucial role in myocardial electrical excitation. Single-channel recordings indicate that these channels exhibit functional interactions and coupled gating. However, the analysis of such recordings often involves manual interventions, leading to potential bias. In this study, an automated pipeline was developed to de-trend and idealize single-channel currents, revealing weak or no functional interactions in wild-type Na(v)1.5 channels.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Biochemistry & Molecular Biology
Oksana Iamshanova, Jean-Sebastien Rougier, Hugues Abriel
Summary: Clusters of the α-subunit of voltage-gated sodium channels play a crucial role in cellular excitability and action potential propagation. In cardiomyocytes, the α-subunit Na(v)1.5 is expressed at specialized membrane microdomains. The mechanisms underlying the redistribution and cooperativity of Na(v)1.5 remain unclear, but interactions with β-subunits and 14-3-3 proteins are thought to be involved.
Meeting Abstract
Biophysics
Oksana Iamshanova, Arbresh Seljmani, Elise Ramaye, Sabrina Guichard, Maria Essers, Anne-Flore Hammerli, Jean-Sebastien Rougier, Hugues Abriel
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(2021)
Meeting Abstract
Biochemistry & Molecular Biology
O. Iamshanova, A. Seljmani, E. Ramaye, S. Guichard, M. Essers, A. Hammerli, J. Rougier, H. Abriel
Article
Biochemistry & Molecular Biology
Zizun Wang, Sarah H. Vermij, Valentin Sottas, Anna Shestak, Daniela Ross-Kaschitza, Elena Zaklyazminskaya, Andy Hudmon, Geoffrey S. Pitt, Jean-Sebastien Rougier, Hugues Abriel