Identification of a Novel Structural Class of H1 Inhibitors by Structure-Based Virtual Screening.

The human voltage-gated proton channel, hH1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of H1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hH1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structure-based virtual screening on an open structure of the human H1 channel.

A synthetic flavonoid derivate in the plasma membrane transforms the voltage-clamp fluorometry signal of CiHv1.

Voltage-clamp fluorometry (VCF) enables the study of voltage-sensitive proteins through fluorescent labeling accompanied by ionic current measurements for voltage-gated ion channels. The heterogeneity of the fluorescent signal represents a significant challenge in VCF. The VCF signal depends on where the cysteine mutation is incorporated, making it difficult to compare data among different mutations and different studies and standardize their interpretation.

Elucidation of the binding mode of organic polysulfides on the human TRPA1 receptor.

Previous studies have established that endogenous inorganic polysulfides have significant biological actions activating the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor. Organic polysulfides exert similar effects, but they are much more stable molecules, therefore these compounds are more suitable as drugs. In this study, we aimed to better understand the mechanism of action of organic polysulfides by identification of their binding site on the TRPA1 receptor.

Molecular rearrangements in S6 during slow inactivation in Shaker-IR potassium channels.

Voltage-gated K+ channels have distinct gates that regulate ion flux: the activation gate (A-gate) formed by the bundle crossing of the S6 transmembrane helices and the slow inactivation gate in the selectivity filter. These two gates are bidirectionally coupled. If coupling involves the rearrangement of the S6 transmembrane segment, then we predict state-dependent changes in the accessibility of S6 residues from the water-filled cavity of the channel with gating.

Elasto-plastic analysis and optimal design of composite integral abutment bridge extended with limited residual plastic deformation.

Due to the growing significance of structural theories concerning the composite structure analysed and designed plastically, this paper introduces a new optimisation method for controlling the plastic behaviour of a full-scale composite integral abutment bridge by employing complementary strain energy of residual forces that existed within the reinforcing rebars. Composite bridges are structures made of components such as steel and concrete, which are frequent and cost-effective building methods. Thus, various objective functions were used in this work when applying optimum elasto-plastic analysing and designing the composite integrated bridge structure that was tested experimentally in the laboratory.

New 'kids' on the voltage-gated proton channel block.

So far one gene for Hv1 has been detected in studied species. The work presented by Chaves et al. in The FEBS Journal reported an 'Unexpected expansion of the voltage-gated proton channel family'.

Multiple mechanisms contribute to fluorometry signals from the voltage-gated proton channel.

Voltage-clamp fluorometry (VCF) supplies information about the conformational changes of voltage-gated proteins. Changes in the fluorescence intensity of the dye attached to a part of the protein that undergoes a conformational rearrangement upon the alteration of the membrane potential by electrodes constitute the signal. The VCF signal is generated by quenching and dequenching of the fluorescence as the dye traverses various local environments.

Investigation of the Role of the TRPA1 Ion Channel in Conveying the Effect of Dimethyl Trisulfide on Vascular and Histological Changes in Serum-Transfer Arthritis.

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases. Its therapy is often challenging, even in the era of biologicals. Previously, we observed the anti-inflammatory effects of garlic-derived organic polysulfide dimethyl trisulfide (DMTS).

Functional Voltage-Gated Sodium Channels Are Present in the Human B Cell Membrane.

B cells express various ion channels, but the presence of voltage-gated sodium (Na) channels has not been confirmed in the plasma membrane yet. In this study, we have identified several Na channels, which are expressed in the human B cell membrane, by electrophysiological and molecular biology methods. The sensitivity of the detected sodium current to tetrodotoxin was between the values published for TTX-sensitive and TTX-insensitive channels, which suggests the co-existence of multiple Na1 subtypes in the B cell membrane.

Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation.

The human voltage gated potassium channel Kv1.5 that conducts the I current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF.

A Novel Insecticidal Spider Peptide that Affects the Mammalian Voltage-Gated Ion Channel hKv1.5.

Spider venoms include various peptide toxins that modify the ion currents, mainly of excitable insect cells. Consequently, scientific research on spider venoms has revealed a broad range of peptide toxins with different pharmacological properties, even for mammal species. In this work, thirty animal venoms were screened against hK1.

[Clinical aspects and therapeutic possibilities of neurogenic bladder].

Összefoglaló. Az alsó húgyutak fő funkciója a vizelet tárolása és ürítése, amely működések zavara az úgynevezett alsó húgyúti tünetegyüttes kialakulásához vezet, ami a kiváltó októl függően vizeletürítési zavarral és vizeletretencióval is járhat. Kezeletlen esetekben a felső húgyutak károsodása következik be a magas hólyagnyomás által kiváltott vesicoureteralis reflux következtében, amely ureter- és veseüregrendszeri tágulat kialakulására, illetve fertőzésekre és kőképződésre hajlamosít.

The activation gate controls steady-state inactivation and recovery from inactivation in Shaker.

Despite major advances in the structure determination of ion channels, the sequence of molecular rearrangements at negative membrane potentials in voltage-gated potassium channels of the Shaker family remains unknown. Four major composite gating states are documented during the gating process: closed (C), open (O), open-inactivated (OI), and closed-inactivated (CI). Although many steps in the gating cycle have been clarified experimentally, the development of steady-state inactivation at negative membrane potentials and mandatory gating transitions for recovery from inactivation have not been elucidated.

The voltage-gated proton channel hHv1 is functionally expressed in human chorion-derived mesenchymal stem cells.

The voltage-gated proton channel Hv1 is widely expressed, among others, in immune and cancer cells, it provides an efficient cytosolic Hextrusion mechanism and regulates vital functions such as oxidative burst, migration and proliferation. Here we demonstrate the presence of human Hv1 (hHv1) in the placenta/chorion-derived mesenchymal stem cells (cMSCs) using RT-PCR. The voltage- and pH-dependent gating of the current is similar to that of hHv1 expressed in cell lines and that the current is blocked by 5-chloro-2-guanidinobenzimidazole (ClGBI) and activated by arachidonic acid (AA).

Periodic Membrane Potential and Ca Oscillations in T Cells Forming an Immune Synapse.

The immunological synapse (IS) is a specialized contact area formed between a T cell and an antigen presenting cell (APC). Besides molecules directly involved in antigen recognition such as the TCR/CD3 complex, ion channels important in the membrane potential and intracellular free Ca concentration control of T cells are also recruited into the IS. These are the voltage-gated Kv1.

TMEM266 is a functional voltage sensor regulated by extracellular Zn.

Voltage-activated ion channels contain S1-S4 domains that sense membrane voltage and control opening of ion-selective pores, a mechanism that is crucial for electrical signaling. Related S1-S4 domains have been identified in voltage-sensitive phosphatases and voltage-activated proton channels, both of which lack associated pore domains. hTMEM266 is a protein of unknown function that is predicted to contain an S1-S4 domain, along with partially structured cytoplasmic termini.

Membrane Potential Distinctly Modulates Mobility and Signaling of IL-2 and IL-15 Receptors in T Cells.

The high electric field across the plasma membrane might influence the conformation and behavior of transmembrane proteins that have uneven charge distributions in or near their transmembrane regions. Membrane depolarization of T cells occurs in the tumor microenvironment and in inflamed tissues because of K release from necrotic cells and hypoxia affecting the expression of K channels. However, little attention has been given to the effect of membrane potential (MP) changes on membrane receptor function.

[Maternal and neonatal vitamin B deficiency detected by expanded newborn screening].

Introduction: Infant vitamin B deficiency can manifest as a severe neurodegenerative disorder and is usually caused by maternal deficiency due to vegetarian diet or pernicious anaemia. Its early recognition and treatment can prevent potentially serious and irreversible neurologic damage. Biochemically, vitamin B deficiency leads to an accumulation of methylmalonic acid, homocysteine, and propionylcarnitine.

A new mechanism of voltage-dependent gating exposed by K10.1 channels interrupted between voltage sensor and pore.

Voltage-gated ion channels couple transmembrane potential changes to ion flow. Conformational changes in the voltage-sensing domain (VSD) of the channel are thought to be transmitted to the pore domain (PD) through an α-helical linker between them (S4-S5 linker). However, our recent work on channels disrupted in the S4-S5 linker has challenged this interpretation for the KCNH family.

CTSC and Papillon-Lefèvre syndrome: detection of recurrent mutations in Hungarian patients, a review of published variants and database update.

Papillon-Lefèvre syndrome (PLS; OMIM 245000) is an autosomal recessive condition characterized by palmoplantar hyperkeratosis and periodontitis. In 1997, the gene locus for PLS was mapped to 11q14-21, and in 1999, variants in the cathepsin C gene (CTSC) were identified as causing PLS. To date, a total of 75 different disease-causing mutations have been published for the CTSC gene.

OcyKTx2, a new K⁺-channel toxin characterized from the venom of the scorpion Opisthacanthus cayaporum.

Opisthacanthus cayaporum belongs to the Liochelidae family, and the scorpions from this genus occur in southern Africa, Central America and South America and, therefore, can be considered a true Gondwana heritage. In this communication, the isolation, primary structure characterization, and K⁺-channel blocking activity of new peptide from this scorpion venom are reported. OcyKTx2 is a 34 amino acid long peptide with four disulfide bridges and molecular mass of 3807 Da.

Transient receptor potential vanilloid-2 mediates the effects of transient heat shock on endocytosis of human monocyte-derived dendritic cells.

Our goal was to investigate the effect of heat shock on human monocyte-derived dendritic cells (DCs) and to dissect the role of thermosensitive transient receptor potential (TRP) channels in the process. We provide evidence that a short heat shock challenge (43 °C) decreased the endocytotic activity of the DCs and that this effect could be alleviated by the RNAi-mediated knockdown of TRPV2 but, importantly, not by the pharmacological (antagonists) or molecular (RNAi) suppression of TRPV1 and TRPV4 activities/levels. Likewise, the heat shock-induced robust membrane currents were selectively and markedly inhibited by TRPV2 "silencing" whereas modulation of TRPV1 and TRPV4 activities, again, had no effect.

A novel seven-base deletion of the CTSC gene identified in a Hungarian family with Papillon-Lefèvre syndrome.

Papillon-Lefévre syndrome (PLS; OMIM 245000) is a rare autosomal recessive condition characterized by symmetrical palmoplantar hyperkeratosis and periodontal inflammation, causing loss of both the deciduous and permanent teeth. PLS develops due to mutations in the cathepsin C gene, CTSC. Recently we have identified a Hungarian PLS family with two affected siblings.