A5073506761- Mitochondrial Function and Pathology
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Nitric Oxide and Endothelin Effects
- Cardiac Ischemia and Reperfusion
- ATP Synthase and ATPases Research
- Cardiomyopathy and Myosin Studies
- Neuroscience and Neuropharmacology Research
- Renin-Angiotensin System Studies
- Hormonal Regulation and Hypertension
- Metabolism and Genetic Disorders
- Cardiac Imaging and Diagnostics
- Receptor Mechanisms and Signaling
- Cancer, Lipids, and Metabolism
- Asthma and respiratory diseases
- Chemotherapy-induced cardiotoxicity and mitigation
- Erythrocyte Function and Pathophysiology
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Endoplasmic Reticulum Stress and Disease
- RNA Research and Splicing
- Protein Kinase Regulation and GTPase Signaling
- ECG Monitoring and Analysis
- Adipose Tissue and Metabolism
- Genetic Neurodegenerative Diseases
- IL-33, ST2, and ILC Pathways
University of Iowa
2015-2025
Fraternal Order of Eagles
2022-2024
Iowa City Public Library
2020
Iowa City VA Health Care System
2013-2017
Deutsches Herzzentrum München
2013
Heidelberg University
2011-2013
University Hospital Heidelberg
2011-2013
Baylor College of Medicine
2011-2013
The Ohio State University
2011-2013
Columbia University Irving Medical Center
2010-2012
Background— Atrial fibrillation (AF) is a growing public health problem without adequate therapies. Angiotensin II and reactive oxygen species are validated risk factors for AF in patients, but the molecular pathways connecting unknown. The Ca 2+ /calmodulin-dependent protein kinase (CaMKII) has recently emerged as species–activated proarrhythmic signal, so we hypothesized that oxidized CaMKIIδ could contribute to AF. Methods Results— We found CaMKII was increased atria from patients...
Ion channel function is fundamental to the existence of life. In metazoans, coordinate activities voltage-gated Na(+) channels underlie cellular excitability and control neuronal communication, cardiac excitation-contraction coupling, skeletal muscle function. However, despite decades research linkage dysfunction with arrhythmia, epilepsy, myotonia, little progress has been made toward understanding processes that regulate this family proteins. Here, we have identified β(IV)-spectrin as a...
The identification of nearly a dozen ion channel genes involved in the genesis human atrial and ventricular arrhythmias has been critical for diagnosis treatment fatal cardiovascular diseases. In contrast, very little is known about genetic molecular mechanisms underlying sinus node dysfunction (SND). Here, we report mechanism SND. We mapped two families with highly penetrant severe SND to ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous AnkB phenocopy displayed bradycardia rate variability....
Significance Mitochondrial Ca 2+ is a fundamental signal that allows for adaptation to physiological stress but liability during ischemia-reperfusion injury in heart. On one hand, mitochondrial entry coordinates energy supply and demand myocardium by increasing the activity of matrix dehydrogenases augment ATP production oxidative phosphorylation. other inhibiting overload promulgated as therapeutic approach preserve myocardial tissue following injury. We developed new mouse model...
The best understood "fight or flight" mechanism for increasing heart rate (HR) involves activation of a cyclic nucleotide-gated ion channel (HCN4) by beta-adrenergic receptor (betaAR) agonist stimulation. HCN4 conducts an inward "pacemaker" current (I(f)) that increases the sinoatrial nodal (SAN) cell membrane diastolic depolarization (DDR), leading to faster SAN action potential generation. Surprisingly, knockout mice were recently shown retain physiological HR with isoproterenol (ISO),...
Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart resistant current therapies. However, the metabolic mechanisms driving acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates entry into matrix stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of dominant-negative (DN) MCU. Here, we show that DN-MCU had normal resting rates...
Background— Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia remains undefined despite more than a decade of investigation. Posttranslational modulation proteins is essential normal function. Importantly, aberrant myocyte signaling has been defects in posttranslational modifications and disease. We recently identified novel pathway regulation...
Abstract Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein‐ lipid‐enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca 2+ , lipid, other metabolites between these organelles. Defective MERCs associated with cellular oxidative stress, neurodegenerative disease, cardiac skeletal muscle pathology via mechanisms poorly understood. We previously demonstrated muscle‐specific knockdown (KD) mitochondrial fusion mediator...
Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability myocardial dysfunction remain uncertain. Failing human cardiomyocytes exhibit increased CaMKII voltage-gated Ca 2+ channel (Ca V 1.2) activity, enhanced expression a specific 1.2 β-subunit protein isoform ( β 2a ). We recently identified residues critical phosphorylation (Thr 498) binding (Leu 493),...
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in United States alone. Despite decades of research, surprisingly little known regarding molecular pathways underlying pathogenesis AF. ANK2 encodes ankyrin-B, a multifunctional adapter molecule implicated membrane targeting ion channels, transporters, and signaling molecules excitable cells.In present study, we report early-onset AF harboring loss-of-function mutations ANK2. In mice, show that...
The mitochondrial Ca 2+ uniporter enables ATP production to match energy demands during the cell cycle.
Timothy syndrome (TS) is a disease of excessive cellular Ca(2+) entry and life-threatening arrhythmias caused by mutation in the primary cardiac L-type channel (Ca(V)1.2). The TS causes loss normal voltage-dependent inactivation Ca(V)1.2 current (I(Ca)). During overload, calmodulin-dependent protein kinase II (CaMKII) arrhythmias. We hypothesized that CaMKII part proarrhythmic mechanism TS.We developed an adult rat ventricular myocyte model (G406R) lentivirus-mediated transfer wild-type...
The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows β(2)-adrenergic receptor (β(2)AR) is linked to AMPA-type glutamate subunit GluA1 via stargazin PSD-95 (Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW. EMBO J 29: 482-495, 2010). We now demonstrate β(2)AR plays a prominent role...
Rationale : Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health disease are maintained a complex ensemble intracellular targeting, scaffolding, recycling, degradation pathways. Surprisingly, despite decades research linking dysfunction trafficking with human cardiovascular disease, essentially nothing known regarding the molecular identity or...
Ca 2+ /calmodulin-dependent protein kinase (CaMKII) transduces oxidative stress into asthma-related diseases.
Objective— The main objective of this study is to define the mechanisms by which mitochondria control vascular smooth muscle cell (VSMC) migration and impact neointimal hyperplasia. Approach Results— multifunctional CaMKII (Ca 2+ /calmodulin-dependent kinase II) in mitochondrial matrix VSMC drove a feed-forward circuit with Ca uniporter (MCU) promote influx. MCU was necessary for activation (mtCaMKII), whereas mtCaMKII phosphorylated at regulatory site S92 that promotes entry. sufficient...
Excessive ROS promote allergic asthma, a condition characterized by airway inflammation, eosinophilic and increased hyperreactivity (AHR). The mechanisms which are the relationship between disease phenotypes incompletely defined. Mitochondria an important source of cellular production, our group discovered that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is present in mitochondria activated oxidation. Furthermore, mitochondrial-targeted antioxidant therapy reduced severity asthma...
Rationale: The sodium–calcium exchanger 1 (NCX1) is predominantly expressed in the heart and implicated controlling automaticity isolated sinoatrial node (SAN) pacemaker cells, but potential role of NCX1 determining rate vivo unknown. Objective: To determine Ncx1 rate. Methods Results: We used global myocardial SAN-targeted conditional knockout ( −/− ) mice to measure effect NCX current on pacemaking activity vivo, ex SAN cells. induced using a Cre/loxP system. Unexpectedly, hearts cells...
Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble potassium channels that control myocyte repolarization. While voltage-gated K+ have been well characterized in heart, much less is known about regulation and/or targeting two-pore channel (K2P) family members, despite their potential importance modulation heart function. Here, we report novel molecular pathway for membrane TREK-1, mechano-sensitive K2P by environmental physical factors including...
The coordinated sorting of ion channels to specific plasma membrane domains is necessary for excitable cell physiology. K(ATP) channels, assembled from pore-forming (Kir6.x) and regulatory sulfonylurea receptor subunits, are critical electrical transducers the metabolic state tissues, including skeletal smooth muscle, heart, brain, kidney, pancreas. Here we show that C-terminal domain Kir6.2 contains a motif conferring targeting in primary cells. lacking this displays aberrant channel due...
BK (Maxi-K) channel activity is allosterically regulated by a Ca2+ sensor, formed primarily the channel's large cytoplasmic carboxyl tail segment, and voltage its transmembrane helices. As with other voltage-gated K channels, sensing in accomplished through interactions of S1–S4 segments electric field. However, unique that it contains an additional amino-terminal S0, which important functional interaction between α β subunits. In this study, we used perturbation mutagenesis to analyze role...