@article{pmid40221111,

title = {Excitability properties of cardiac calbindin neurons: Identifying a unique neuronal population},

author = {Guénaëlle Lizot and Jocelyn Bescond and Yves De Koninck and Mohamed Chahine and Patrick Bois and Jean-François Faivre and Aurélien Chatelier},

doi = {10.1016/j.hrthm.2025.04.007},

issn = {1556-3871},

year  = {2026},

date = {2026-03-01},

journal = {Heart Rhythm},

volume = {23},

number = {3},

pages = {741--750},

abstract = {BACKGROUND: The intrinsic cardiac nervous system is a complex system that plays a critical role in the regulation of cardiac physiologic parameters and has been shown to contribute to cardiac arrhythmias. To date, several types of neurons with distinct neurochemical and electrophysiologic phenotypes have been identified. However, no study has correlated the neurochemical phenotype to a specific electrophysiologic behavior. Calbindin-D28k, a calcium-binding protein, is expressed in numerous cardiac neurons.nnOBJECTIVE: Given that changes in neuronal excitability have been associated with arrhythmia susceptibility and that calbindin expression has been associated with modulations of neuronal excitability, our objective was to assess whether the cardiac calbindin neuronal population has specific properties that could be involved in cardiac regulation and arrhythmias.nnMETHODS: By using a Cre-Lox mouse model to specifically target calbindin neurons with a fluorescent reporter, we characterized the neurochemical and electrophysiologic phenotype of this cardiac neuronal population.nnRESULTS: Calbindin neurons exhibit a specific neurochemical expression profile and a larger soma with shorter neurite length compared with other neurons. This was combined with a distinct electrophysiologic signature characterized by a lower excitability with a predominantly phasic profile associated to a lower N-type calcium current density.nnCONCLUSION: Calbindin cardiac neurons display distinct neurochemical, morphologic, and electrophysiologic properties, resembling the cardiac neuronal remodeling observed in pathologic processes such as heart failure. Therefore, we believe that this specific neuronal population deserves investigation in the context of cardiac diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40641062,

title = {Inwardly rectifying potassium channels: Critical insights for insect species and Apis mellifera},

author = {Fabien Sourisseau and Craig A Doupnik and Pierre Charnet and Mohamed Chahine},

doi = {10.1080/19336950.2025.2529250},

issn = {1933-6969},

year  = {2025},

date = {2025-12-01},

journal = {Channels (Austin)},

volume = {19},

number = {1},

pages = {2529250},

abstract = {Kir (inwardly rectifying potassium) channels that play key roles in maintaining potassium homeostasis, neuronal excitability, and osmoregulation have been cloned and characterized in a variety of insects. In , three Kir channels (dKir1 dKir2, and dKir3) have been cloned and characterized, and share significant homology with mammalian Kir channels. The dKir channels are essential for various developmental processes, such as wing patterning, by modulating bone morphogenetic protein signaling pathways. Electrophysiological studies have confirmed that  Kir channels function in a way analogous to their mammalian counterparts, indicating that their roles in cellular and developmental signaling have been evolutionarily conserved. Several Kir channels have also been identified and characterized in mosquitoes ( and ). Interestingly, insect Kir channel orthologs cluster into three gene "clades" or subfamilies (Kir1, Kir2, Kir3) that are distinct from mammal Kir channels based on sequence comparisons. Insect Kir channel paralogs range from two to eight Kir channel genes per species genome representing separate gene duplication events. These differences may be attributed to distinct physiological adaptations associated with their respective taxonomic groups. The honeybee  genome contains two Kir channel genes, AmKir1 and AmKir2, producing six Kir channel isoforms via alternative splicing, which have been cloned and expressed in heterologous systems to study their electrophysiological properties. This review provides a comprehensive overview of current knowledge about Kir channel structures, activities, and gating as well as of their roles in insects, including evolutionary genomic aspects, molecular biology, physiological roles, and pharmacological targeting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41240904,

title = {AAV-mediated DMPK silencing: A defining moment in myotonic dystrophy type 1 therapeutics},

author = {Mohamed Chahine},

doi = {10.1016/j.ymthe.2025.10.063},

issn = {1525-0024},

year  = {2025},

date = {2025-12-01},

journal = {Mol Ther},

volume = {33},

number = {12},

pages = {5933--5935},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41303475,

title = {Cardiac Involvement in Myotonic Dystrophy Type 1: Mechanisms, Clinical Perspectives, and Emerging Therapeutic Strategies},

author = {Vamsi Krishna Murthy Ginjupalli and Jean-Baptiste Reisqs and Michael Cupelli and Mohamed Chahine and Mohamed Boutjdir},

doi = {10.3390/ijms262210992},

issn = {1422-0067},

year  = {2025},

date = {2025-11-01},

journal = {Int J Mol Sci},

volume = {26},

number = {22},

abstract = {Myotonic Dystrophy Type 1 (DM1) is a complex multisystemic genetic disorder caused by CTG repeat expansions in the  gene, leading to RNA toxicity and widespread splicing defects. These splicing abnormalities affect multiple systems, including the respiratory, skeletal, cardiac, nervous, and endocrine systems, resulting in aggressive symptoms that significantly impact quality of life and survival. Cardiac complications are the second leading cause of deaths in DM1, after respiratory insufficiency. Current research is largely focused on understanding cardiac pathology in DM1. This review highlights recent advancements in the clinical and pathological characterization of DM1 cardiac involvement, preclinical models used to study cardiac dysfunction, and emerging therapeutic strategies that target the molecular basis of DM1. Promising approaches include RNA-targeting strategies such as antisense oligonucleotides (ASOs), gene-editing tools like CRISPR-Cas9, and small molecules that modulate RNA splicing. ASOs aim to reduce toxic RNA accumulation, CRISPR-based approaches aim to excise or correct the expanded CTG repeats, and repurposed small-molecule drugs, such as vorinostat, tideglusib, and metformin, could serve as potential therapeutic agents for DM1 patients with cardiac complications. Despite this progress, several challenges remain: the heterogeneity of cardiac manifestations, unpredictable and often silent progression of arrhythmias, limited therapeutic options beyond implantable cardioverter-defibrillator (ICD)/pacemaker implantations, and complex interplay with the multisystemic nature of DM1. More research and well-designed clinical trials are urgently needed to translate these promising strategies into effective treatments for DM1-associated cardiac disease. Here, we discuss the current knowledge in DM1 cardiac pathology and preclinical models as well as the benefits and pitfalls of the available therapeutic approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41006520,

title = {Biophysical and structural insights into the SCN4A E452K variant linked to myotonia and paramyotonia congenita},

author = {Quentin Plumereau and Spencer Lile and Christopher N Johnson and Mohamed Chahine},

doi = {10.1038/s41598-025-17816-2},

issn = {2045-2322},

year  = {2025},

date = {2025-09-01},

journal = {Sci Rep},

volume = {15},

number = {1},

pages = {33101},

abstract = {Myotonia and paramyotonia congenita (PC) are rare neuromuscular disorders characterized by muscle stiffness that intensifies in cold environments. These disorders are associated with variants in the SCN4A gene, that encodes the alpha subunit of the voltage-gated sodium channel Nav1.4. We report here the case of a 36-year-old female who experiences diverse neurological symptoms, including myotonia, cold induced myotonia, resulting in muscle stiffness, and tightness. A whole exome sequencing revealed a missense variant in the SCN4A gene at position c.1354G > A, named p.E452K. We characterized the biophysical properties of this SCN4A variant by overexpressing the wild-type (WT) and mutant channels with the β1 regulatory subunit in HEK293 cells by transfection. Sodium currents were recorded at different temperatures and different extracellular potassium concentrations using the patch-clamp technique. Functional studies of the E452K variant revealed both loss and gain of function phenotypes at different temperatures, which were characterized by a decrease in current density and an increase in the window current. This was related to the shift of inactivation toward more depolarized voltages at both 22 °C and 10 °C and a slower slope factor of activation at 22 °C. A further gain-of-function effect was also observed, which was characterized by a faster onset and recovery from slow inactivation. MD simulation of the alpha subunit in a lipid bilayer suggested that the charge reversal destabilized a native salt bridge (E452-K249). We concluded that the observed enhanced functionality facilitates the activation process, leading to enhanced muscle excitability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40914027,

title = {Functional validation of the Nav1.5/R1432G Brugada syndrome variant using a Nav1.5 knockout iPSC-derived cardiomyocyte model},

author = {Quentin Plumereau and Valérie Pouliot and Mohamed Chahine},

doi = {10.1016/j.bbrc.2025.152586},

issn = {1090-2104},

year  = {2025},

date = {2025-09-01},

journal = {Biochem Biophys Res Commun},

volume = {782},

pages = {152586},

abstract = {Brugada syndrome is a rare inherited cardiac arrhythmia disorder primarily characterized by ventricular fibrillation, which can lead to sudden cardiac death. It follows an autosomal dominant pattern of inheritance and is most associated with dysfunction of the cardiac sodium channel Nav1.5. A novel and physiologically relevant approach to studying Nav1.5 variants involves the use of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes lacking endogenous Nav1.5 expression (Nav1.5 KO). This model allows for precise evaluation of variant-specific effects in a human cardiac cellular context. In this study, we investigated the Nav1.5/R1432G variant, which was previously identified in a patient diagnosed with Brugada syndrome. Sodium currents were recorded using the patch clamp technique in a whole-cell configuration. The Nav1.5/WT channel and the Nav1.5/R1432G variant were labeled by immunocytochemistry. Our results revealed a clear loss-of-function phenotype, consistent with Brugada syndrome. Furthermore, immunocytochemistry demonstrated a significant defect in membrane trafficking of the R1432G variant, supporting the hypothesis that impaired channel surface expression underlies its functional deficit. Action potential analysis revealed a marked reduction in the ventricular depolarization rate, consistent with impaired sodium channel function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39260661,

title = {Exploring SCN5A variants associated with atrial fibrillation in atrial cardiomyocytes derived from human induced pluripotent stem cells: A characterization study},

author = {Marion Pierre and Mohammed Djemai and Valérie Pouliot and Hugo Poulin and Michael H Gollob and Mohamed Chahine},

doi = {10.1016/j.hrthm.2024.09.013},

issn = {1556-3871},

year  = {2025},

date = {2025-06-01},

journal = {Heart Rhythm},

volume = {22},

number = {6},

pages = {1574--1587},

abstract = {BACKGROUND: Atrial fibrillation (AF) poses a major risk for heart failure, myocardial infarction, and stroke. Several studies have linked SCN5A variants to AF, but their precise mechanistic contribution remains unclear. Human induced pluripotent stem cells (hiPSCs) provide a promising platform for modeling AF-linked SCN5A variants and their functional alterations.nnOBJECTIVE: The purpose of this study was to assess the electrophysiological impact of 3 AF-linked SCN5A variants (K1493R, M1875T, N1986K) identified in 3 unrelated individuals.nnMETHODS: CRISPR-Cas9 was used to generate a new hiPSC line in which Na1.5 was knocked out. Following differentiation into specific atrial cardiomyocyte by using retinoic acid, the adult wild-type (WT) and 3 AF variants were introduced into the Na1.5 knockout (KO) line through transfection. Subsequent analysis including molecular biology, optical mapping, and electrophysiology were performed.nnRESULTS: The absence of Na1.5 channels altered the expression of key cardiac genes. Na1.5 KO atrial-like cardiomyocytes derived from human induced pluripotent stem cells displayed slower conduction velocities, altered action potential (AP) parameters, and impaired calcium transient propagation. The transfection of the WT channel restored sodium current density, AP characteristics and the expression of several cardiac genes. Among the AF variants, 1 induced a loss of function (N1986K) while the other 2 induced a gain of function in Na1.5 channel activity. Cellular excitability alterations and early afterdepolarizations were observed in AF variants.nnCONCLUSION: Our findings suggest that distinct alterations in Na1.5 channel properties may trigger altered atrial excitability and arrhythmogenic activity in AF. Our KO model offers an innovative approach for investigating SCN5A variants in an adult human cardiac environment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39471665,

title = {Generation of a control induced pluripotent stem cell line (CBRCULi014-A) derived from the lymphoblastoid cells of a pediatric individual},

author = {Thiéry De Serres-Bérard and Valérie Pouliot and Jack Puymirat and Mohamed Chahine},

doi = {10.1016/j.scr.2024.103587},

issn = {1876-7753},

year  = {2024},

date = {2024-12-01},

journal = {Stem Cell Res},

volume = {81},

pages = {103587},

abstract = {Lymphoblastoid cell lines serve as a readily and continuous resource for generating induced pluripotent stem cells (iPSCs), enabling the modeling of various genetic disorders in vitro. When investigating congenital and infantile diseases, age-matched controls derived from pediatric individuals are typically necessary, yet they may be scarce or difficult to obtain. Here, the Sendai virus system was employed to introduce reprogramming factors into lymphoblastoid cells derived from an apparently healthy 4-year-old female. The generated iPSCs strongly expressed pluripotency cell markers and displayed robust trilineage differentiation. CBRCULi014-A is therefore a reliable control iPSC line for pediatric disease investigation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39551029,

title = {Generation of an iPSC cell line (VANYHHi001-A) from a patient with cardiac arrythmias carrying CACNA1D, SCN5A, and DSP variants},

author = {Yvonne Sleiman and Jean-Baptiste Reisqs and Reina Bianca Tan and Frank Cecchin and Mohamed Chahine and Mohamed Boutjdir},

doi = {10.1016/j.scr.2024.103608},

issn = {1876-7753},

year  = {2024},

date = {2024-12-01},

journal = {Stem Cell Res},

volume = {81},

pages = {103608},

abstract = {Progressive cardiac conduction defect often associated with variants in sodium voltage-gated channel SCN5A gene and variants in the L-type calcium voltage-gated channel CACNA1D gene are implicated in sinoatrial node dysfunction. We generated an induced pluripotent stem cell line (iPSC) from a 13-year-old patient with history of conduction system disease and ventricular tachycardia, carrying variants in SCN5A (c.2618C > G), CACNA1D (c.3786G > T), and DSP (c.1582C > G). The generated iPSC line exhibited pluripotency markers, differentiated into the three embryonic germ layers, and maintained a normal karyotype. This iPSC line offers insights into the pathophysiological mechanisms of cardiac arrhythmias and personalized therapies development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39617325,

title = {Unravelling impacts of the insecticide deltamethrin on neuronal sodium channels in honey bees: Molecular insights and behavioural outcomes},

author = {Aklesso Kadala and Mahira Kaabeche and Mercédès Charreton and Jérôme Mutterer and Michel Pélissier and Thierry Cens and Matthieu Rousset and Mohamed Chahine and Pierre Charnet and Claude Collet},

doi = {10.1016/j.chemosphere.2024.143852},

issn = {1879-1298},

year  = {2024},

date = {2024-12-01},

journal = {Chemosphere},

volume = {369},

pages = {143852},

abstract = {The current risk assessment framework for insecticides suffers from certain shortcomings in adequately addressing the effects of low doses on off-target species. To remedy this gap, a combination of behavioural assays and in vitro cellular approaches are required to refine the precision of toxicity assessment. The domestic honey bee has long been standing as an emblematic pollinator in ecotoxicology, and once more, it provides us with a practical testing model for this purpose. First, newly emerged bees (D1) were found more vulnerable than 6 days-old bees (D6) to deltamethrin, a widely used α-cyano-3-phenoxybenzyle pyrethroid. In D1 bees, the range of doses inducing mortality was shifted towards lower values (∼2-fold) with a correspondingly lower LD (11 ng/bee). Moreover, at low doses that do not induce mortality in laboratory conditions, the locomotor behaviour of D1 bees was more impacted than in D6 bees. This was evidenced by an increase in immobility time and a decrease in locomotor performance across all tested doses for D1 bees (0.75, 1.5 and 3 ng/bee) during automated 21 h-long observations. Behavioural disorders are linked to deltamethrin's disruption of voltage-gated sodium channels (Nas) functions, as quantified in cultured neuronal cells. In the presence of deltamethrin, patch-clamp experiments revealed a concentration- and a use-dependent slowing of Na kinetics. Channel's deactivation is slowed by three orders of magnitude at 10 μM deltamethrin. Two additional phenoxybenzyle pyrethroids, including the commonly used cypermethrin, elicited quantitatively similar effects on Na kinetics. The integration of in vitro cellular assays and behavioural assays may facilitate a deeper understanding and prediction of insecticides toxicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}