Topic
Voltage/patch clamp
About: Voltage/patch clamp is a research topic. Over the lifetime, 12 publications have been published within this topic receiving 254 citations.
Papers
TL;DR: 2D-QSTR and toxicophore models provide a useful framework for understanding binding, and gave structural insight into the specific protein-ligand interactions responsible for affinity, and how one might modify any given structure to mitigate binding.
Abstract: Predictive quantitative structure-toxicity and toxicophore models were developed for a diverse series of hERG K+ channel blockers, acting as anti-arrhythmic agents using QSAR+ module in Cerius2 and HypoGen module in Catalyst software, respectively. The 2D-QSTR analysis has been performed on a dataset of 68 molecules carefully selected from literature for which IC50 values measured on hERG K+ channels expressed in mammalian cells lines using the voltage patch clamp assay technique were reported. Their biological data, expressed as IC50, spanned from 7.0nM to 1.4mM, with 7 orders difference. Several types of descriptors including electrotopological, thermodynamic, ADMET, graph theoretical (topological and information content) were used to derive a quantitative relationship between the channel blockers and its physico-chemical properties. Statistically significant QSTR model was obtained using genetic function approximation methodology, having seven descriptors, with a correlation coefficient (r2) of 0.837, cross-validated correlation coefficient (q2) of 0.776 and predictive correlation coefficient (r2 pred) of 0.701, indicating the robustness of the model. Toxicophore model generated using HypoGen module in Catalyst, on these datasets, showed three important features for hERG K+ channel blockers, (i) hydrophobic group (HP), (ii) ring aromatic group (RA) and (iii) hydrogen bond acceptor lipid group (HBAl). The most predictive hypothesis (Hypo 1), consisting of these three features had a best correlation coefficient of 0.820, a low rms deviation of 1.740, and a high cost difference of 113.50, which represents a true correlation and a good predictivity. The hypothesis, Hypo 1 was validated by a test set consisting of 12 molecules and by a cross-validation of 95% confidence level. Accordingly, our 2D-QSTR and toxicophore model has strong predictivity to identify structurally diverse hERG K+ channel blockers with desired biological activity. These models provide a useful framework for understanding binding, and gave structural insight into the specific protein-ligand interactions responsible for affinity, and how one might modify any given structure to mitigate binding.
48 citations
TL;DR: It was found that the neuron-like cells differentiated from the BMSCs-D-NSCs could express positive NeuN, synthesize and excrete amino acids, and show some typical electrophysiological properties.
Abstract: The transversal differentiation of bone marrow stroma cell (BMSCs) into neural stem cells (NSCs) has attracted much attention in recent years because of their therapeutic potential. However, the problem in therapeutic application of NSCs was how to confirm whether neuron-like cells differentiated from bone marrow stroma cell-derived neural stem cells (BMSCs-D-NSCs) possess corresponding functions of neurochemistry and electrophysiology. In the present study, we tried to affirm the function of neuron-like cells differentiated from BMSCs-D-NSCs in vitro. The BMSCs were harvested by gradient centrifugation in Ficoll-Paque and cultured in "NSCs medium". Immunocytochemistry was used to detect positive expression of neuron-specific nuclear protein (NeuN) in neuron-like cells derived from the BMSCs-D-NSCs. High-pressure liquid chromatography (HPLC) was used to identify neuron-like cells by detecting excitable amino acids [aspartic acid (Asp), glutamic acid (Glu)], inhibited amino acids [glycine (Gly), gamma (gamma) -aminobutyric acid (GABA), alanine (Ala)] or monoamines [noradrenaline (NE), 5-hydroxytryptamine (5-HT), dopamine (DA)]. Electrophysiological properties of the neuron-like cells were also examined using patch clamp analysis to verify their neuron-like functions. It was found that the neuron-like cells differentiated from the BMSCs-D-NSCs could express positive NeuN, synthesize and excrete amino acids, and show some typical electrophysiological properties including the typical Na+ and K+ ion channel membrane current under the voltage patch clamp condition, the typical static electrical membrane potential under the current patch clamp condition, and the differential membrane capacitance and resistance values in series between undifferentiated BMSCs-D-NSCs and differentiated neuron-like cells under the whole-cell patch clamp condition. The neuron-like cells differentiated from BMSCs-D-NSCs exhibit both neuron-like biochemical function and some corresponding electrophysiological properties.
22 citations
TL;DR: A mechanism-based, Hodgkin-Huxley-type modeling approach is proposed that allows connecting the key parameters of experimental voltage-/patch-clamp data directly to the major control values of the model, and can be physiologically justified and makes the model easier to handle, especially in context with experimental data.
9 citations
TL;DR: The aim of this study was to analyze the block of HERG‐carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmmic activity, in transfected mouse fibroblasts.
Abstract: Introduction: The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts.
Methods and Results: Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns.
Conclusion: We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered. (J Cardiovasc Electrophysiol, Vol. 14, pp. 651-658, June 2003)
6 citations
TL;DR: Results suggest that 5-HT(1A/7) receptor agonist causes "disinhibition" of T-AVPNs, which might, in part, account for the reflex increase of airway resistance.
5 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2013 | 2 |
| 2012 | 4 |
| 2011 | 1 |
| 2008 | 2 |
| 2003 | 1 |