A5041276453- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Neuroscience and Neural Engineering
- Cardiomyopathy and Myosin Studies
- Neurobiology and Insect Physiology Research
- Neuroscience of respiration and sleep
- Mitochondrial Function and Pathology
- Neural dynamics and brain function
- Atrial Fibrillation Management and Outcomes
- Cardiovascular Effects of Exercise
- Protein Kinase Regulation and GTPase Signaling
- Electrochemical Analysis and Applications
- Photoreceptor and optogenetics research
- Cardiac pacing and defibrillation studies
- Cardiac Arrhythmias and Treatments
- Nicotinic Acetylcholine Receptors Study
- Biotin and Related Studies
- Cardiac Ischemia and Reperfusion
- Neonatal and fetal brain pathology
- Insect and Pesticide Research
- Adenosine and Purinergic Signaling
- ECG Monitoring and Analysis
- Anesthesia and Neurotoxicity Research
Columbia University
2009-2024
Emory University Hospital
2015-2021
Georgetown University
1996-2017
Georgetown University Medical Center
1996-2017
Columbia University Irving Medical Center
2017
New York Proton Center
2016
New York University
2010-2011
Critical Path Institute
2005
University of Central Florida
2005
United States Food and Drug Administration
2005
We have evaluated the ability of various opioid agonists, including methadone, l-α-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block cardiac human <i>ether-a-go-go</i>-related gene (HERG) K<sup>+</sup>current (I<sub>HERG</sub>) in cells stably transfected with HERG potassium channel gene. Our results show that LAAM, buprenorphine were effective inhibitors I<sub>HERG</sub>, IC<sub>50</sub> values 1 10 μM range. The other drugs tested far less potent...
Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses methadone cause torsades de pointes. To date, no controlled study has described an association between QTc prolongation. The only commercial formulation parenteral available in United States contains preservative chlorobutanol....
Background —Atrial fibrillation (AF) is frequently associated with atrial dilatation caused by pressure or volume overload. Stretch-activated channels (SACs) have been found in myocardial cells and may promote AF dilated atria. To prove this hypothesis, we investigated the effect of SAC blocker gadolinium (Gd 3+ ) on propensity isolated rabbit heart during stretch. Methods Results —In 16 Langendorff-perfused hearts, interatrial septum was perforated to equalize biatrial pressures. Caval...
MAP Recordings from Mouse Heart. Introduction: The monophasic action potential (MAP) technique has been validated in humans and larger animals, but, mice, recordings available to date show little resemblance the murine ventricular transmembrane (TAP) measured by conventional microelectrodes. We developed a miniaturized contact electrode establish isolated mouse hearts: (1) optimal size; (2) validation against TAP; (3) relationship between repolarization refractoriness; (4) regional...
The purpose of the present study was to comparatively evaluate human <i>HERG</i> currents and QT intervals following challenge with suspected torsadogenic nontorsadogenic drugs. Various concentrations 14 different drugs were initially evaluated in terms their relative potency block I<sub>HERG</sub> stably transfected embryonic kidney cells. Four general categories identified: high-potency blockers (IC<sub>50</sub> < 0.1 μM) included lidoflazine, terfenadine, haloperidol; moderate-potency...
1. The cause of the increased frequency glutamatergic miniature excitatory postsynaptic currents (mEPSCs) resulting from anoxia was investigated in CA1 neurons vitro rat hippocampal slice. These were examined by whole-cell patch-clamp recording, and hypoxia induced switching perfusion slice oxygenated artificial cerebral spinal fluid (ACSF) to ACSF saturated with 95% N2-5% O2. Except where noted, experiments carried out containing 1 microM tetrodotoxin (TTX). 2. Although resulted a...
Increased sodium influx via incomplete inactivation of the major cardiac channel Na(V)1.5 is correlated with an increased incidence atrial fibrillation (AF) in humans. Here, we sought to determine whether entry sufficient cause structural and electrophysiological perturbations that are required initiate sustain AF. We used mice expressing a human variant mutation anesthetic-binding site (F1759A-Na(V)1.5) demonstrated Na+ drive alterations, including ventricular enlargement, myofibril...
Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover primary mechanism underlying heart's innate reserve. We show that four protein kinase A (PKA)-phosphorylated residues Rad, a calcium channel inhibitor, are crucial for controlling basal current essential β-adrenergic augmentation of influx cardiomyocytes. Even with intact PKA signaling to other proteins modulating handling, preventing adrenergic activation...
The ability to fight or flee from a threat relies upon an acute adrenergic surge that augments cardiac output, which is dependent increased contractility and heart rate. This response depends on β-adrenergic-initiated reversal of the small RGK G-protein Rad-mediated inhibition voltage-gated calcium channels (CaV) acting through Cavβ subunit. Here, we investigate how Rad couples phosphorylation augmented Ca2+ influx contraction. We show requires Ser272 Ser300 within Rad's polybasic,...
1. The effect of hypoxia on synaptic physiology was investigated in hippocampal slices from 16- to 23-day-old rats. CA1 pyramidal cells were examined by whole cell patch-clamp recording, and induced switching perfusion the slice oxygenated artificial cerebrospinal fluid (ACSF) ACSF saturated with 95% N2-5%CO2. Synaptic responses assessed stimulating Schaffer collateral-commissural projection an electrode stratum radiatum every 20 s. 2. Within 100-200 s onset hypoxia, orthrodromically...
The cardiac voltage-gated Ca2+ channel, Cav1.2, mediates excitation-contraction coupling in the heart. molecular composition of channel includes pore-forming α1 subunit and auxiliary α2/δ-1 β subunits. γ subunits, which there are 8 isoforms, consist 4 transmembrane domains with intracellular N- C-terminal ends. γ1 was initially detected skeletal muscle Cav1.1 complex, modulating current amplitude activation inactivation properties. also shifts steady-state to more negative membrane...
Ca2+ channel β-subunit interactions with pore-forming α-subunits are long-thought to be obligatory for trafficking the cell surface and tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression mutant α1C subunits lacking capacity bind CaVβ can traffic sarcolemma adult cardiomyocytes vivo sustain normal excitation-contraction coupling. However, these β-less channels cannot stimulated by β-adrenergic pathway agonists, thus adrenergic...
Rationale: Changing activity of cardiac Ca V 1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant physiology pathophysiology. Although are prominently upregulated via activation PKA (protein kinase A), essential molecular details remained stubbornly enigmatic. Objective: The primary goal this study was to determine how various factors converging at the I-II loop interact regulate channel β-adrenergic stimulation, failure. Methods...
Diabetes mellitus and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation altered electric properties, manifested by prolongation the QRS duration QT interval. It is difficult to distinguish contribution from global metabolic defects incidence death abnormalities.In order study effects abnormalities on arrhythmias without complex systemic diabetes we studied transgenic mice cardiac-specific overexpression peroxisome...
Rationale: Sympathetic nervous system triggered activation of protein kinase A, which phosphorylates several targets within cardiomyocytes, augments inotropy, chronotropy, and lusitropy. An important target β-adrenergic stimulation is the sarcolemmal L-type Ca 2+ channel, V 1.2, plays a key role in cardiac excitation–contraction coupling. The molecular mechanisms regulation 1.2 however, are incompletely known. Recently, it has been postulated that proteolytic cleavage at Ala 1800 A...
Significance Calcium influx through the cardiac voltage-dependent L-type calcium channel (Ca V 1.2) increases during “fight or flight” activation of β-adrenergic and protein kinase A (PKA) signaling pathway. None previously identified sites in α 1C subunit, each painstakingly singly investigated, were shown to be required for adrenergic modulation Ca 1.2. Our approach allowed an unprecedented massive increase throughput, because we mutated many potential PKA phosphorylation throughout . By...
The regulation of Ca(2+) influx through the phosphorylation L-type channel, Ca(v)1.2, is important for modulation excitation-contraction (E-C) coupling in heart. Ca(v)1.2 thought to be target multiple kinases that mediate signals both renin-angiotensin and sympathetic nervous systems. Detailed biochemical information regarding protein reactions involved limited. kinase C (PKC) family can modulate cardiac contractility a complex manner, such either enhanced or depressed relaxation accelerated...
Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity mortality. Recently, we created a mouse model with spontaneous sustained AF caused by mutation in NaV1.5 channel (F1759A) that enhances persistent Na+ current, thereby enabling investigation of molecular mechanisms cause identification potentially novel treatment strategies. The mice have regional heterogeneity action potential duration atria similar to observations patients AF. In these...
Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, development of which requires improved understanding cellular signaling pathways that facilitate structural and electrophysiological remodeling occurs in atria. Similar to humans, increased persistent Na+ current leads an myopathy spontaneous long-lasting episodes AF mice. How causes both atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with...
Recent clinical observations indicate that female gender is associated with a higher risk of developing torsades de pointes (TdP) cardiac arrhythmia. In this study, we used the Langendorff technique in isolated perfused rabbit hearts and whole-cell patch-clamp ventricular myocytes to examine difference TdP incidence gain insight into underlying mechanisms. Isolated were by using technique. was induced abrupt changes cycle length (deltaCL) presence Tyrode's solution containing 1 mM...
1. We investigated the mechanism of hypoxia-induced depression gamma-aminobutyric acid-A (GABAA)-mediated inhibitory postsynaptic currents (IPSCs) in CA1 neurons hippocampal slices from 21- to 28-day-old rats. Cells were examined by whole-cell patch-clamp recording and hypoxia was induced switching perfusion slice oxygenated artificial cerebral spinal fluid (ACSF) ACSF saturated with 95% N2-5% CO2. 2. Synaptic responses evoked stimulation Schaffer collateral-commissural projection at a fixed...
Hypoxia induces depression of excitatory postsynaptic currents (EPSCs) and inhibitory (IPSCs) in CA1 neurons the hippocampus. The effect antagonists that act at A1 adenosine receptor on hypoxia-induced EPSCs IPSCs were examined hippocampal slices with patch clamp technique (whole-cell configuration). 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (200 nM) 8-phenyltheophilline (8-PT) (10 μM) significantly prevented by hypoxia but failed to protect IPSCs. This result suggests EPSC involves...