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1	Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel NaV1.5 Gulsevin, Alican, Glazer, Andrew M., Shields, Tiffany, Kroncke, Brett M., Roden, Dan M., Meiler, Jens 20 January 2024 (has links) The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine (VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we perform docking calculations and high-throughput electrophysiology experiments in the present study. The docking calculations identified two distinct binding regions. The first site was in the pore, close to the binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409, E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect, consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an allosteric inactivation mechanism for VTD at NaV1.5 info:eu-repo/classification/ddc/610 ddc:610
2	Neurotoxins and Neurotoxic Species Implicated in Neurodegeneration Segura-Aguilar, Juan, Kostrzewa, Richard M. 01 December 2004 (has links) Neurotoxins, in the general sense, represent novel chemical structures which when administered in vivo or in vitro, are capable of producing neuronal damage or neurodegeneration - with some degree of specificity relating to neuronal phenotype or populations of neurons with specific characteristics (.e., receptor type, ion channel type, astrocyte-dependence, etc.). The broader term 'neurotoxin' includes this categorization but extends the term to include intra- or extracellular mediators involved in the neurodegenerative event, including necrotic and apoptotic factors. Moreover, as it is recognized that astrocytes are essential supportive satellite cells for neurons, and because damage to these cells ultimately affects neuronal function, the term 'neurotoxin' might reasonably be extended to include those chemical species which also adversely affect astrocytes. This review is intended to highlight developments that have occurred in the field of 'neurotoxins' during the past 5 years, including MPTP/MPP+, 6-hydroxydopamine (6-OHDA), meth-amphetamine; salsolinol; leukoaminochrome-o-semi-quinone; rotenone; iron; paraquat; HPP+; veratridine; soman; glutamate; kainate; 3-nitropropionic acid; peroxynitrite anion; and metals (copper, manganese, lead, mercury). Neurotoxins represent tools to help elucidate intra- and extra-cellular processes involved in neuronal necrosis and apoptosis, so that drugs can be developed towards targets that interrupt the processes leading towards neuronal death. 3-nitropropionicacid 6-OHDA apoptosis copper domoate glutamate HPP + iron kainate lead leukoaminochrome-o-semiquinone manganese mercury methamphetamine MPP + MPTP necrosis neurodegeneration neurotoxins paraquat peroxynitriteanion rotenone salsolinol soman veratridine Biomedical Sciences

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Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel NaV1.5

Neurotoxins and Neurotoxic Species Implicated in Neurodegeneration