A5006064421- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neural Engineering
- Neuroscience and Neuropharmacology Research
- Cardiomyopathy and Myosin Studies
- Receptor Mechanisms and Signaling
- Pain Mechanisms and Treatments
- Electrochemical Analysis and Applications
- Cardiovascular Effects of Exercise
- Genetic Neurodegenerative Diseases
- Genomics and Rare Diseases
- Nicotinic Acetylcholine Receptors Study
- Neurological disorders and treatments
- Cardiac Arrhythmias and Treatments
- Photoreceptor and optogenetics research
- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Genetics and Neurodevelopmental Disorders
- Ion Channels and Receptors
- Cardiac Fibrosis and Remodeling
- Connexins and lens biology
- Signaling Pathways in Disease
- Analytical Methods in Pharmaceuticals
- Congenital heart defects research
University of Maryland, Baltimore
2016-2025
University of Maryland, College Park
2018-2024
Johns Hopkins Medicine
2008-2021
Johns Hopkins University
2008-2021
University of Baltimore
2015-2020
Miami Children's Hospital
2016
Mayo Clinic
2016
Merck & Co., Inc., Rahway, NJ, USA (United States)
2004-2006
Merck (Japan)
2004
University of North Carolina at Chapel Hill
2003
Calmodulinopathies comprise a new category of potentially life-threatening genetic arrhythmia syndromes capable producing severe long-QT syndrome (LQTS) with mutations involving CALM1, CALM2, or CALM3. The underlying basis this form LQTS is disruption Ca2+/calmodulin (CaM)-dependent inactivation L-type Ca2+ channels.To gain insight into the mechanistic underpinnings calmodulinopathies and devise therapeutic strategies for treatment LQTS.We generated characterized functional properties...
Abstract Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. The underlying defect single de novo missense mutation in Ca V 1.2 channels, either G406R or G402S. Notably, these mutations are often viewed as equivalent, they produce comparable defects voltage-dependent inactivation and cause similar manifestations patients. Yet, their effects on calcium-dependent (CDI) have remained...
The discovery of novel therapeutic agents that act on voltage-gated sodium channels requires the establishment high-capacity screening assays can reliably measure activity these proteins. Fluorescence resonance energy transfer (FRET) technology using membrane potential-sensitive dyes has been shown to provide a readout channel in stably transfected cell lines. Due inherent rapid inactivation channels, require presence activator prolong opening. Because activators and test compounds may share...
CaV1.3 channels are a major class of L-type Ca(2+) which contribute to the rhythmicity heart and brain. In brain, these vital for excitation-transcription coupling, synaptic plasticity, neuronal firing. Moreover, disruption function has been associated with several neurological disorders. Here, we focus on de novo missense mutation A760G linked autism spectrum disorder (ASD). To explore role this in ASD pathogenesis, examined effects channel gating regulation. Introduction severely...
Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback cellular excitability in neurons cardiomyocytes. Yet this modularity counters functional adaptability, global changes ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 cysteine-rich domain (stac) fibroblast growth factor homologous factors (fhf)...
Abstract The regulation of L-type Ca 2+ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this in cardiac V 1.2 channels, relatively little is known about the closely related 1.4 which feature prominently visual system. Here we find that are indeed modulated PKA phosphorylation inhibitor -dependent inactivation (ICDI) motif. Phosphorylation region promotes occupancy...
In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over 10-year period. Each child died suddenly unexpectedly during sleep period, at ages ranging from 19 days to 18 months. 2019 we were asked investigate if genetic cause could explain the children's deaths as part inquiry into mother's convictions.Whole genomes or exomes mother sequenced. Functional analysis novel CALM2 variant performed measuring Ca2+-binding affinity, interaction with calcium...
Abstract Background Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Initially, was characterized cardiac presentation of long QT and syndactyly fingers and/or toes, all associated with variant, Gly406Arg. However, subsequent identification diverse has expanded clinical spectrum, revealing various extra-cardiac manifestations. It remains underexplored whether individuals canonical Gly406Arg mutually exclusive exon 8A (Timothy 1) or 8 2) exhibit...
Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties <i>trans</i>-<i>N</i>-{[2′-(aminosulfonyl)biphenyl-4-yl]methyl}-<i>N</i>-methyl-<i>N</i>′-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting blocker. In whole-cell...
The first pathogenic mutation in CaV1.2 was identified 2004 and shown to cause a severe multisystem disorder known as Timothy syndrome (TS). localized the distal S6 region of channel, play major role channel activation. TS patients suffer from life-threatening cardiac symptoms well significant neurodevelopmental deficits, including autism spectrum (ASD). Since this discovery, number variety mutations have grown tremendously, regions remain frequent locus for many these mutations. While...
Voltage-gated potassium (Kv) currents of human pancreatic islet cells were studied by whole-cell patch clamp recording. On average, 75% the tested identified as beta-cells single cell, post-recording RT-PCR for insulin mRNA. In most cells, dominant Kv current was a delayed rectifier. The rectifier activated at potentials above -20 mV and had V(1/2) activation -5.3 mV. Onset inactivation slow major component (tau = 3.2 s +20 mV) observed in all cells; smaller 0.30 s) with an amplitude...