A5008339680- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Receptor Mechanisms and Signaling
- Signaling Pathways in Disease
- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Neuroscience and Neuropharmacology Research
- Calcium signaling and nucleotide metabolism
- Muscle Physiology and Disorders
- Adipose Tissue and Metabolism
- Cardiac Arrhythmias and Treatments
- Mitochondrial Function and Pathology
- Ion Channels and Receptors
- Education Systems and Policy
- Pancreatic function and diabetes
- Protein Kinase Regulation and GTPase Signaling
- Neuroscience and Neural Engineering
- Atrial Fibrillation Management and Outcomes
- Health and Medical Research Impacts
- Cardiac Ischemia and Reperfusion
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Cardiovascular and exercise physiology
- Youth Education and Societal Dynamics
- Toxin Mechanisms and Immunotoxins
Columbia University
2015-2024
Columbia University Irving Medical Center
2015-2023
Columbia College
2006-2021
Royal College of Physicians
2006-2021
Australian Football League
2017-2018
Manchester City Football Club
2017
New York Proton Center
2013
Marks and Spencer (United Kingdom)
2013
Academy of Athens
2012
National and Kapodistrian University of Athens
2012
Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by β adrenergic receptor (βAR) activation, which increases the slow outward potassium ion current ( I KS ). Mutations in two human channel subunits, hKCNQ1 and hKCNE1, prolong APD cause inherited arrhythmias known as LQTS (long QT syndrome). We show that βAR modulation requires targeting adenosine 3′,5′-monophosphate (cAMP)–dependent protein kinase (PKA) phosphatase 1 (PP1) to through yotiao....
The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Using site-directed mutagenesis, we identified specific Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation site recombinant RyR2, distinct from A (PKA) that mediates "fight-or-flight" stress response. CaMKII increased RyR2 Ca2+ sensitivity and open probability. was activated at heart rates, which may contribute to enhanced...
Abstract Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound its cytosolic receptor FKBP, is an immunosuppressant a potent inhibitor of cellular proliferation. In present study, antiproliferative effects rapamycin on human rat were examined compared with related immunosuppressant, FK520. cells, at concentrations as low 1 ng/mL, inhibited DNA synthesis growth. FK520, analogue FK506,...
Endoplasmic reticulum (ER) stress-induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and calcium release apoptosis, we hypothesized that involves activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-alpha (ER oxidase 1 alpha). In ER-stressed cells, induced by CHOP, small interfering RNA (siRNA) knockdown suppresses apoptosis. IP3-induced (IICR)...
The calcium release channel (CRC)/ryanodine receptor (RyRec) has been identified as the foot structure of sarcoplasmic reticulum (SR) and provides pathway for efflux required excitation-contraction coupling in skeletal muscle. CRC previously reported to consist four identical 565-kDa protomers. We now report identification a 12-kDa protein which is tightly associated with highly purified RyRec from rabbit muscle SR. N-terminal amino acid sequencing cDNA cloning demonstrates that fast twitch...
Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty accelerated arteriopathy cardiac transplantation. Previously, we reported that macrolide antibiotic rapamycin, but not related compound FK506, inhibits both human rat aortic SMC in vitro by inhibiting cycle-dependent kinases delaying phosphorylation retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, A.R. Marks. 1995....
Background —Although percutaneous transluminal coronary angioplasty (PTCA) is a highly effective procedure to reduce the severity of stenotic atherosclerotic disease, its long-term success significantly limited by high rate restenosis. Several cellular and molecular mechanisms have been implicated in development restenosis post-PTCA, including vascular smooth muscle cell (VSMC) activation, migration, proliferation. Recently, our group demonstrated that rapamycin, an immunosuppressant agent...
Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, major source of energy, in form ATP, required cardiac contractility, are closely interconnected with SR, and Ca2+ essential optimal function these organelles. However, accumulation can impair mitochondrial function, leading to reduced ATP production increased release reactive oxygen species (ROS). Oxidative stress contributes heart failure (HF), but whether plays a...
Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and those underlying disease such as heart failure. In animals failure inherited forms of exercise-induced SCD, depletion the channel-stabilizing protein calstabin2 (FKBP12.6) from ryanodine receptor–calcium release channel (RyR2) complex causes an intracellular Ca 2+ leak that trigger fatal arrhythmias. A derivative 1,4-benzothiazepine (JTV519) increased affinity for RyR2, which stabilized closed...
Background— Cardiac transplantation vasculopathy is the leading cause of late death in heart recipients. Rapamycin an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression graft 46 patients (age, 54±10 years; 4.3±2.3 years after transplantation) severe disease. Methods Results— At annual cardiac catheterization, were randomly assigned to treatment (n=22) versus continued current immunosuppression (n=24)....
Excitation-contraction coupling in skeletal muscle requires the release of intracellular calcium ions (Ca 2+ ) through ryanodine receptor (RyR1) channels sarcoplasmic reticulum. Half RyR1 are activated by voltage-dependent Ca plasma membrane. In planar lipid bilayers, exhibited simultaneous openings and closings, termed “coupled gating.” Addition channel accessory protein FKBP12 induced coupled gating, removal uncoupled channels. Coupled gating provides a mechanism which that not associated...
Excitation-contraction coupling in heart muscle requires the activation of Ca(2+)-release channels/type 2 ryanodine receptors (RyR2s) by Ca(2+) influx. RyR2s are arranged on sarcoplasmic reticular membrane closely packed arrays such that their large cytoplasmic domains contact one another. We now show multiple can be isolated under conditions they remain physically coupled to When these channels examined planar lipid bilayers, exhibit simultaneous gating, termed "coupled gating." Removal...
The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and also present brain. Mutations RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated mutations result “leaky” channels due decreased binding of calstabin2 (FKBP12.6) subunit, which stabilizes closed state channel. We found that mice heterozygous R2474S mutation Ryr2 (Ryr2-R2474S mice)...
Defective regulation of the cardiac ryanodine receptor (RyR2)/calcium release channel, required for excitation-contraction coupling in heart, has been linked to arrhythmias and heart failure. For example, diastolic calcium “leak” via RyR2 channels sarcoplasmic reticulum identified as an important factor contributing impaired contractility failure ventricular that cause sudden death. In patients with failure, chronic activation “fight or flight” stress response leads protein kinase A (PKA)...