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Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers.
Trads JB, Hüll K, Matsuura BS, Laprell L, Fehrentz T, Görldt N, Kozek KA, Weaver CD, Klöcker N, Barber DM, Trauner D
(2019) Angew Chem Int Ed Engl 58: 15421-15428
MeSH Terms: Action Potentials, Azo Compounds, Cyclization, Drug Design, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, Humans, Isomerism, Lidocaine, Light, Patch-Clamp Techniques, Potassium Channel Blockers, Thermodynamics
Show Abstract · Added March 27, 2020
Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
1 Members
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13 MeSH Terms
On the Relationship between MRI and Local Field Potential Measurements of Spatial and Temporal Variations in Functional Connectivity.
Shi Z, Wilkes DM, Yang PF, Wang F, Wu R, Wu TL, Chen LM, Gore JC
(2019) Sci Rep 9: 8871
MeSH Terms: Action Potentials, Animals, Brain Mapping, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Saimiri, Somatosensory Cortex, Spatio-Temporal Analysis
Show Abstract · Added July 11, 2019
Correlations between fluctuations in resting state BOLD fMRI signals are interpreted as measures of functional connectivity (FC), but the neural basis of their origins and their relationships to specific features of underlying electrophysiologic activity, have not been fully established. In particular, the dependence of FC metrics on different frequency bands of local field potentials (LFPs), and the relationship of dynamic changes in BOLD FC to underlying temporal variations of LFP correlations, are not known. We compared the spatial profiles of resting state coherences of different frequency bands of LFP signals, with high resolution resting state BOLD FC measurements. We also compared the probability distributions of temporal variations of connectivity in both modalities using a Markov chain model-based approach. We analyzed data obtained from the primary somatosensory (S1) cortex of monkeys. We found that in areas 3b and 1 of S1 cortex, low frequency LFP signal fluctuations were the main contributions to resting state LFP coherence. Additionally, the dynamic changes of BOLD FC behaved most similarly to the LFP low frequency signal coherence. These results indicate that, within the S1 cortex meso-scale circuit studied, resting state FC measures from BOLD fMRI mainly reflect contributions from low frequency LFP signals and their dynamic changes.
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8 MeSH Terms
SCN5A variant R222Q generated abnormal changes in cardiac sodium current and action potentials in murine myocytes and Purkinje cells.
Daniel LL, Yang T, Kroncke B, Hall L, Stroud D, Roden DM
(2019) Heart Rhythm 16: 1676-1685
MeSH Terms: Action Potentials, Alleles, Animals, Disease Models, Animal, Echocardiography, Electrocardiography, Mice, Mice, Transgenic, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Purkinje Cells, Sodium Channels
Show Abstract · Added June 14, 2019
BACKGROUND - The cardiac sodium channel (SCN5A) mutation R222Q neutralizes a positive charge in the domain I voltage sensor. Mutation carriers display very frequent ectopy and dilated cardiomyopathy.
OBJECTIVES - To describe the effect of SCN5A R222Q on murine myocyte and Purkinje fiber electrophysiology, and identify underlying mechanisms.
METHODS - We generated mice carrying humanized wild-type (H) and mutant (RQ) SCN5A channels. We characterized whole-heart and isolated ventricular and Purkinje myocyte properties.
RESULTS - RQ/RQ mice were not viable. I from RQ/H ventricular myocytes displayed increased "window current" and hyperpolarizing shifts in both inactivation and activation compared to H/H, as previously reported in heterologous expression systems. Surprisingly, action potentials were markedly abbreviated in RQ/H myocytes (action potential durations at 90% repolarization: 12.6 ± 1.3 ms vs 29.1 ± 1.0 ms in H/H, P < .01, n = 10 each). We identified a large [K]-dependent outward gating pore current in RQ/H but not H/H myocytes, and decreasing [K] elicited early afterdepolarizations (EADs) and triggered activity in isolated myocytes and ectopic beats in whole hearts. Further, RQ/H Purkinje cells displayed striking, consistent low-voltage EADs. In vivo, however, RQ/H mice displayed little ectopy and contractile function was normal.
CONCLUSION - While SCN5A R222Q increases plateau inward sodium current, action potentials were unexpectedly shortened, likely reflecting an outward gating-pore current. Low extracellular potassium increased this pore current, and was arrhythmogenic in vitro and ex vivo.
Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
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12 MeSH Terms
Electrophysiologic and molecular mechanisms of a frameshift NPPA mutation linked with familial atrial fibrillation.
Menon A, Hong L, Savio-Galimberti E, Sridhar A, Youn SW, Zhang M, Kor K, Blair M, Kupershmidt S, Darbar D
(2019) J Mol Cell Cardiol 132: 24-35
MeSH Terms: Action Potentials, Animals, Atrial Fibrillation, Atrial Natriuretic Factor, Electrophysiological Phenomena, Frameshift Mutation, Heart Atria, Humans, Membrane Potentials, Mice, Mice, Transgenic, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel
Show Abstract · Added June 14, 2019
A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na (NaV1.5) and Ca (CaV1.2/CaV1.3) channel expression and currents (I, I) and action potential durations (APD/APD/APD) were significantly reduced in H-fsMut-NPPA mice while the rectifier K channel current (I) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na, Ca and K channels creating an electrophysiologic substrate for reentrant AF.
Copyright © 2019 Elsevier Ltd. All rights reserved.
1 Communities
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13 MeSH Terms
Patient-independent human induced pluripotent stem cell model: A new tool for rapid determination of genetic variant pathogenicity in long QT syndrome.
Chavali NV, Kryshtal DO, Parikh SS, Wang L, Glazer AM, Blackwell DJ, Kroncke BM, Shoemaker MB, Knollmann BC
(2019) Heart Rhythm 16: 1686-1695
MeSH Terms: Action Potentials, Calcium Channels, L-Type, Child, Clustered Regularly Interspaced Short Palindromic Repeats, Female, Gene Editing, Genetic Testing, Genetic Variation, Humans, Induced Pluripotent Stem Cells, Long QT Syndrome, Pedigree, Phenotype
Show Abstract · Added March 4, 2020
BACKGROUND - Commercial genetic testing for long QT syndrome (LQTS) has rapidly expanded, but the inability to accurately predict whether a rare variant is pathogenic has limited its clinical benefit. Novel missense variants are routinely reported as variant of unknown significance (VUS) and cannot be used to screen family members at risk for sudden cardiac death. Better approaches to determine the pathogenicity of VUS are needed.
OBJECTIVE - The purpose of this study was to rapidly determine the pathogenicity of a CACNA1C variant reported by commercial genetic testing as a VUS using a patient-independent human induced pluripotent stem cell (hiPSC) model.
METHODS - Using CRISPR/Cas9 genome editing, CACNA1C-p.N639T was introduced into a previously established hiPSC from an unrelated healthy volunteer, thereby generating a patient-independent hiPSC model. Three independent heterozygous N639T hiPSC lines were generated and differentiated into cardiomyocytes (CM). Electrophysiological properties of N639T hiPSC-CM were compared to those of isogenic and population control hiPSC-CM by measuring the extracellular field potential (EFP) of 96-well hiPSC-CM monolayers and by patch clamp.
RESULTS - Significant EFP prolongation was observed only in optically stimulated but not in spontaneously beating N639T hiPSC-CM. Patch-clamp studies revealed that N639T prolonged the ventricular action potential by slowing voltage-dependent inactivation of Ca1.2 currents. Heterologous expression studies confirmed the effect of N639T on Ca1.2 inactivation.
CONCLUSION - The patient-independent hiPSC model enabled rapid generation of functional data to support reclassification of a CACNA1C VUS to likely pathogenic, thereby establishing a novel LQTS type 8 mutation. Furthermore, our results indicate the importance of controlling beating rates to evaluate the functional significance of LQTS VUS in high-throughput hiPSC-CM assays.
Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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1 Members
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13 MeSH Terms
Intrinsic functional architecture of the non-human primate spinal cord derived from fMRI and electrophysiology.
Wu TL, Yang PF, Wang F, Shi Z, Mishra A, Wu R, Chen LM, Gore JC
(2019) Nat Commun 10: 1416
MeSH Terms: Action Potentials, Animals, Electrophysiological Phenomena, Haplorhini, Humans, Magnetic Resonance Imaging, Physical Stimulation, Reproducibility of Results, Rest, Spinal Cord, Spinal Cord Dorsal Horn, Touch
Show Abstract · Added July 11, 2019
Resting-state functional MRI (rsfMRI) has recently revealed correlated signals in the spinal cord horns of monkeys and humans. However, the interpretation of these rsfMRI correlations as indicators of functional connectivity in the spinal cord remains unclear. Here, we recorded stimulus-evoked and spontaneous spiking activity and local field potentials (LFPs) from monkey spinal cord in order to validate fMRI measures. We found that both BOLD and electrophysiological signals elicited by tactile stimulation co-localized to the ipsilateral dorsal horn. Temporal profiles of stimulus-evoked BOLD signals covaried with LFP and multiunit spiking in a similar way to those observed in the brain. Functional connectivity of dorsal horns exhibited a U-shaped profile along the dorsal-intermediate-ventral axis. Overall, these results suggest that there is an intrinsic functional architecture within the gray matter of a single spinal segment, and that rsfMRI signals at high field directly reflect this underlying spontaneous neuronal activity.
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2 Members
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MeSH Terms
The expanding roles and mechanisms of G protein-mediated presynaptic inhibition.
Zurawski Z, Yim YY, Alford S, Hamm HE
(2019) J Biol Chem 294: 1661-1670
MeSH Terms: Action Potentials, Biochemistry, History, 20th Century, History, 21st Century, Humans, Periodicals as Topic, Presynaptic Terminals, Receptors, G-Protein-Coupled, Synaptic Transmission
Show Abstract · Added March 24, 2020
Throughout the past five decades, tremendous advancements have been made in our understanding of G protein signaling and presynaptic inhibition, many of which were published in the under the tenure of Herb Tabor as Editor-in-Chief. Here, we identify these critical advances, including the formulation of the ternary complex model of G protein-coupled receptor signaling and the discovery of Gβγ as a critical signaling component of the heterotrimeric G protein, along with the nature of presynaptic inhibition and its physiological role. We provide an overview for the discovery and physiological relevance of the two known Gβγ-mediated mechanisms for presynaptic inhibition: first, the action of Gβγ on voltage-gated calcium channels to inhibit calcium influx to the presynaptic active zone and, second, the direct binding of Gβγ to the SNARE complex to displace synaptotagmin downstream of calcium entry, which has been demonstrated to be important in neurons and secretory cells. These two mechanisms act in tandem with each other in a synergistic manner to provide more complete spatiotemporal control over neurotransmitter release.
© 2019 Zurawski et al.
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1 Members
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A current understanding of drug-induced QT prolongation and its implications for anticancer therapy.
Roden DM
(2019) Cardiovasc Res 115: 895-903
MeSH Terms: Action Potentials, Animals, Antineoplastic Agents, Genetic Predisposition to Disease, Heart Conduction System, Heart Rate, Humans, Long QT Syndrome, Membrane Transport Proteins, Molecular Targeted Therapy, Prognosis, Risk Assessment, Risk Factors
Show Abstract · Added March 24, 2020
The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
0 Communities
1 Members
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13 MeSH Terms
Multiple mechanisms underlie increased cardiac late sodium current.
Kroncke BM, Yang T, Roden DM
(2019) Heart Rhythm 16: 1091-1097
MeSH Terms: Action Potentials, Animals, CHO Cells, Cardiac Conduction System Disease, Cricetinae, Cricetulus, Genotype, Humans, Induced Pluripotent Stem Cells, Kidney, Long QT Syndrome, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Phosphatidylinositol 3-Kinases
Show Abstract · Added March 26, 2019
BACKGROUND - We recently reported a quantitative relationship between the degree of functional perturbation reported in the literature for 356 variants in the cardiac sodium channel gene SCN5A and the penetrance of resulting arrhythmia phenotypes. In the course of that work, we identified multiple SCN5A variants, including R1193Q, that are common in populations but are reported in human embryonic kidney (HEK) cells to generate large late sodium current (I).
OBJECTIVE - The purpose of this study was to compare the functional properties of R1193Q with those of the well-studied type 3 long QT syndrome mutation ΔKPQ.
METHODS - We compared functional properties of SCN5A R1193Q with those of ΔKPQ in Chinese hamster ovary (CHO) cells at baseline and after exposure to intracellular phosphatidylinositol (3,4,5)-trisphosphate (PIP), which inhibits I generated by decreased Phosphoinositide 3-kinase (PI3K) activity. We also used CRISPR/Cas9 editing to generate R1193Q in human-induced pluripotent stem cells differentiated to cardiomyocytes (hiPSC-CMs).
RESULTS - Both R1193Q and ΔKPQ generated robust I in CHO cells. PIP abrogated the late current phenotype in R1193Q cells but had no effect on ΔKPQ. Homozygous R1193Q hiPSC-CMs displayed increased I and long action potentials with frequent triggered beats, which were reversed with the addition of PIP.
CONCLUSION - The consistency between the late current produced in HEK cells, CHO cells, and hiPSC-CMs suggests that the late current is a feature of the SCN5A R1193Q variant in human cardiomyocytes but that the mechanism by which the late current is produced is distinct and indirect, as compared with the more highly penetrant ΔKPQ. These data suggest that observing a late current in an in vitro setting does not necessarily translate to highly pathogenic type 3 long QT syndrome phenotype but depends on the underlying mechanism.
Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
0 Communities
3 Members
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15 MeSH Terms
Functional Categories of Visuomotor Neurons in Macaque Frontal Eye Field.
Lowe KA, Schall JD
(2018) eNeuro 5:
MeSH Terms: Action Potentials, Animals, Attention, Eye Movements, Frontal Lobe, Macaca radiata, Male, Neurons, Reaction Time, Visual Fields, Visual Pathways
Show Abstract · Added March 18, 2020
Frontal eye field (FEF) in macaque monkeys contributes to visual attention, visual-motor transformations and production of eye movements. Traditionally, neurons in FEF have been classified by the magnitude of increased discharge rates following visual stimulus presentation, during a waiting period, and associated with eye movement production. However, considerable heterogeneity remains within the traditional visual, visuomovement, and movement categories. Cluster analysis is a data-driven method of identifying self-segregating groups within a dataset. Because many cluster analysis techniques exist and outcomes vary with analysis assumptions, consensus clustering aggregates over multiple analyses, identifying robust groups. To describe more comprehensively the neuronal composition of FEF, we applied a consensus clustering technique for unsupervised categorization of patterns of spike rate modulation measured during a memory-guided saccade task. We report 10 functional categories, expanding on the traditional 3 categories. Categories were distinguished by latency, magnitude, and sign of visual response; the presence of sustained activity; and the dynamics, magnitude and sign of saccade-related modulation. Consensus clustering can include other metrics and can be applied to datasets from other brain regions to provide better information guiding microcircuit models of cortical function.
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