Induced pluripotent stem cell (iPSC)-derived motor neurons provide a powerful platform for studying motor neuron diseases. These cells enable human-specific modeling of disease mechanisms and high-throughput drug screening. While commercially available iPSC-derived motor neurons offer a convenient alternative to time-intensive differentiation protocols, their electrophysiological properties and maturation require comprehensive evaluation to validate their utility for research and therapeutic applications. In this study, we characterized the electrophysiological properties of commercially available iPSC-derived motor neurons. Immunofluorescence confirmed the expression of motor neuron-specific biomarkers, indicating successful differentiation and maturation. Electrophysiological recordings revealed stable passive membrane properties, maturation-dependent improvements in action potential kinetics, and progressive increases in repetitive firing. Voltage-clamp analyses confirmed the functional expression of key ion channels, including high- and low-voltage-activated calcium channels, TTX-sensitive and TTX-insensitive sodium channels, and voltage-gated potassium channels. While the neurons exhibited hallmark features of motor neuron physiology, high input resistance, depolarized resting membrane potentials, and limited firing capacity suggest incomplete electrical maturation. Altogether, these findings underscore the potential of commercially available iPSC-derived motor neurons as a practical resource for MND research, while highlighting the need for optimized protocols to support prolonged culture and full maturation.

• Klíčová slova
• Motor neuron, action potential, calcium current, iPSC, potassium current, sodium current,
• MeSH
• akční potenciály účinky léků   MeSH
• buněčná diferenciace MeSH
• elektrofyziologické jevy MeSH
• indukované pluripotentní kmenové buňky * cytologie   metabolismus   MeSH
• lidé MeSH
• motorické neurony * metabolismus   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Elevated plasma homocysteine (Hcy) levels lead to hyperhomocysteinemia, a condition associated with various neurological disorders affecting multiple brain regions, including the hippocampus. In this study, we investigated the effects of exposing cultured rat hippocampal neurons to Hcy concentrations corresponding to mild, moderate, and severe hyperhomocysteinemia. A short 24-hour exposure had minimal effects, whereas prolonged exposure up to 14 days moderately enhanced hippocampal excitability without altering the gene expression of voltage-dependent calcium, sodium, or potassium channels or intracellular calcium levels. These findings suggest that Hcy-induced changes in neuronal excitability may contribute to neuropathologies associated with hyperhomocysteinemia.

• Klíčová slova
• Hippocampal excitability, Hyperhomocysteinemia, Intracellular calcium, Transcriptomics, Voltage gated ion channels,
• MeSH
• hipokampus * cytologie   účinky léků   MeSH
• homocystein * farmakologie   MeSH
• iontové kanály * genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• neurony * účinky léků   metabolismus   cytologie   MeSH
• potkani Sprague-Dawley MeSH
• regulace genové exprese * účinky léků   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• homocystein * MeSH
• iontové kanály * MeSH
• vápník MeSH

Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.

• Klíčová slova
• CACNA1C, Calcium channel, Cav1.2, Channelopathies, Electrophysiology, L658P,
• MeSH
• dítě MeSH
• gating iontového kanálu * MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• molekulární modely MeSH
• neurovývojové poruchy * genetika   MeSH
• předškolní dítě MeSH
• sekvence aminokyselin MeSH
• vápníkové kanály - typ L * genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• CACNA1C protein, human MeSH Prohlížeč
• vápníkové kanály - typ L * MeSH

STUDY OBJECTIVES: Sleep-disordered breathing and diabetes mellitus (DM) are often concomitant; however, data on the impact of sleep-disordered breathing on mortality in the population with diabetes remain scarce. METHODS: The population from the Sleep Heart Health Study, a multicenter prospective observational study representing 5,780 patients with polysomnography and mortality data, including 453 patients with DM, was analyzed to assess the impact of sleep-disordered breathing variables and the presence of DM on all-cause, cardiovascular disease, and noncardiovascular disease associated mortality. Survival analysis and proportional hazard regression models were used to calculate the adjusted hazard ratios (aHRs) for mortality. RESULTS: Patients with DM and the average oxygen saturation > 91.4% had significantly lower all-cause (aHR 0.52, confidence interval [CI] 0.34-0.80) and cardiovascular disease mortality risk (aHR 0.44, CI 0.22-0.87) as compared with patients with oxygen saturation below this value. Apnea-hypopnea index > 31 (aHR 1.58, CI 1.10-2.28) and oxygen desaturation index > 13.3 (aHR 1.58, CI 1.10-2.25) were associated with increased all-cause mortality in participants with DM on treatment. Sleep efficiency and proportion of rapid eye movement sleep did not have any impact on mortality in patients with DM and thus differed significantly from individuals without DM, where increased all-cause mortality was observed in those with sleep efficiency < 81.4% (aHR 0.77, CI 0.68-0.87) or rapid eye movement sleep < 14.9% (aHR 0.78, CI 0.68-0.89). CONCLUSIONS: Patients with diabetes on treatment and moderate to severe sleep-disordered breathing experience increased all-cause mortality. Reduced average oxygen saturation predicted both all-cause and cardiovascular death in the population with diabetes. CITATION: Vichova T, Petras M, Waldauf P, Westlake K, Vimmerova-Lattova Z, Polak J. Sleep-disordered breathing increases mortality in patients with diabetes. J Clin Sleep Med. 2025;21(1):89-99.

• Klíčová slova
• cardiovascular disease, diabetes mellitus, mortality, oxygen saturation, sleep-disordered breathing,
• MeSH
• diabetes mellitus * mortalita   epidemiologie   MeSH
• kardiovaskulární nemoci mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polysomnografie * statistika a číselné údaje   MeSH
• prospektivní studie MeSH
• senioři MeSH
• syndromy spánkové apnoe * mortalita   komplikace   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.

• Klíčová slova
• Calcium channels, Channelosome, Ion channels, T-type channels,
• MeSH
• blokátory kalciových kanálů MeSH
• neurony metabolismus   MeSH
• vápník * metabolismus   MeSH
• vápníkové kanály - typ T * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• blokátory kalciových kanálů MeSH
• vápník * MeSH
• vápníkové kanály - typ T * MeSH

Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.

• Klíčová slova
• Amyotrophic lateral sclerosis, Ion channels, Motor neurons, Neurodegeneration, Neuronal excitability,
• MeSH
• amyotrofická laterální skleróza * MeSH
• iontové kanály MeSH
• lidé MeSH
• motorické neurony MeSH
• svalová slabost MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• iontové kanály MeSH

Missense mutations in the human secretary carrier-associated membrane protein 5 (SCAMP5) cause a variety of neurological disorders including neurodevelopmental delay, epilepsy, and Parkinson's disease. We recently documented the importance of SCAMP2 in the regulation of T-type calcium channel expression in the plasma membrane. Here, we show that similar to SCAMP2, the co-expression of SCAMP5 in tsA-201 cells expressing recombinant Cav3.1, Cav3.2, and Cav3.3 channels nearly abolished whole-cell T-type currents. Recording of intramembrane charge movements revealed that SCAMP5-induced inhibition of T-type currents is primarily caused by the reduced expression of functional channels in the plasma membrane. Moreover, we show that SCAMP5-mediated downregulation of Cav3.2 channels is essentially preserved with disease-causing SCAMP5 R91W and G180W mutations. Hence, this study extends our previous findings with SCAMP2 and indicates that SCAMP5 also contributes to repressing the expression of T-type channels in the plasma membrane.

• Klíčová slova
• Calcium channels, Channelopathy, Ion channels, SCAMP5, Secretory carrier-associated membrane protein 5, T-type channels,
• MeSH
• buněčná membrána MeSH
• down regulace MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace MeSH
• vápníkové kanály - typ T * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• membránové proteiny MeSH
• SCAMP5 protein, human MeSH Prohlížeč
• vápníkové kanály - typ T * MeSH

T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss-apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.

• Klíčová slova
• CACNA1H, Calcium channels, Cav3.2, Channelopathy, Epilepsy, Hearing, Ion channels, Mutation, T-type channels,
• MeSH
• epilepsie * genetika   MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mutace genetika   MeSH
• nedoslýchavost * MeSH
• vápníkové kanály MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• vápníkové kanály MeSH

BACKGROUND: COVID-19, an infectious disease caused by SARS-CoV-2, was shown to be associated with an increased risk of new-onset diabetes. Mechanisms contributing to the development of hyperglycemia are still unclear. We aimed to study whether hyperglycemia is related to insulin resistance and/or beta cell dysfunction. MATERIALS AND METHODS: Survivors of severe COVID-19 but without a known history of diabetes were examined at baseline (T0) and after 3 (T3) and 6 (T6) months: corticosteroids use, indirect calorimetry, and OGTT. Insulin response and sensitivity (IS) were expressed as insulinogenic (IGI), disposition (DI), and Matsuda insulin sensitivity index (ISI). Resting energy expenditure (REE) and respiratory quotient (RQ) was calculated from the gas exchange and nitrogen losses. RESULTS: 26 patients (out of 37) with complete outcome data were included in the analysis (age ~59.0 years; BMI ~ 30.4, 35% women). Patients were hypermetabolic at T0 (30.3 ± 4.0 kcal/kg lean mass/day, ~120% predicted) but REE declined over 6 months (ΔT6-T0 mean dif. T6-T0 (95% CI): -5.4 (-6.8, -4.1) kcal/kg FFM/day, p < 0.0001). 17 patients at T0 and 13 patients at T6 had hyperglycemia. None of the patients had positive islet autoantibodies. Insulin sensitivity in T0 was similarly low in hyperglycemic (H) and normoglycemic patients (N) (T0 ISIH = 3.12 ± 1.23, ISIN = 3.47 ± 1.78, p = 0.44), whereas insulin response was lower in the H group (DIH = 3.05 ± 1.79 vs DIN = 8.40 ± 5.42, p = 0.003). Over 6 months ISI (ΔT6-T0 mean dif. T6-T0 for ISI (95% CI): 1.84 (0.45, 3.24), p = 0.01)) increased in the H group only. CONCLUSIONS: Patients with severe COVID-19 had increased REE and insulin resistance during the acute phase due to the infection and corticosteroid use, but these effects do not persist during the follow-up period. Only patients with insufficient insulin response developed hyperglycemia, indicating that beta cell dysfunction, rather than insulin resistance, was responsible for its occurrence.

• MeSH
• COVID-19 * komplikace   MeSH
• hyperglykemie * MeSH
• inzulin MeSH
• inzulinová rezistence * fyziologie   MeSH
• krevní glukóza MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• SARS-CoV-2 MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inzulin MeSH
• krevní glukóza MeSH

• MeSH
• analgezie * MeSH
• bolest farmakoterapie   MeSH
• COVID-19 * MeSH
• lidé MeSH
• neuropilin-1 metabolismus   MeSH
• receptory vaskulárního endoteliálního růstového faktoru metabolismus   MeSH
• SARS-CoV-2 metabolismus   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• komentáře MeSH
• úvodníky MeSH
• Názvy látek
• neuropilin-1 MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• vaskulární endoteliální růstový faktor A MeSH