A5087989619- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Neuroscience and Neural Engineering
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Cardiac pacing and defibrillation studies
- Lipid Membrane Structure and Behavior
- Advanced biosensing and bioanalysis techniques
- ECG Monitoring and Analysis
- Cardiomyopathy and Myosin Studies
- Wireless Body Area Networks
- Chemical Synthesis and Analysis
- Semiconductor materials and devices
- Molecular Communication and Nanonetworks
- Congenital heart defects research
- Phosphodiesterase function and regulation
- Marine Toxins and Detection Methods
- Heart Rate Variability and Autonomic Control
- Pluripotent Stem Cells Research
- Cardiac Arrhythmias and Treatments
- Nicotinic Acetylcholine Receptors Study
- Advanced Memory and Neural Computing
- Protein Kinase Regulation and GTPase Signaling
- Signaling Pathways in Disease
- Botulinum Toxin and Related Neurological Disorders
University of Colorado Anschutz Medical Campus
2015-2024
National Institute of Neurological Disorders and Stroke
2023-2024
National Institutes of Health
2023-2024
Columbia University
2023-2024
University of Montana
2024
University of Colorado Denver
2012-2024
The Medical Center of Aurora
2011-2013
University of Colorado System
2011
Harvard University
2004-2006
Colorado State University
2000-2002
Direct reprogramming of fibroblasts into cardiomyocytes by forced expression cardiomyogenic factors, GMT (GATA4, Mef2C, Tbx5) or GHMT Hand2, Tbx5), has recently been demonstrated, suggesting a novel therapeutic strategy for cardiac repair. However, current approaches are inefficient. Here we demonstrate that pro-fibrotic signalling potently antagonizes reprogramming. Remarkably, inhibition using small molecules target the transforming growth factor-β Rho-associated kinase pathways converts...
Significance Maximum heart rate (mHR) declines with age, contributing to the reduced aerobic capacity of elderly. A parallel reduction in "intrinsic rate" (which is measured during autonomic blockade) underlies decline mHR, and indicates that pacemaker function sinoatrial node compromised aging. In this study we demonstrate slower rates elderly result from depressed spontaneous activity individual myocytes (SAMs). Patch-clamp electrophysiology revealed aged SAMs have slowed AP firing rates,...
Spontaneous rhythmic activity in mammalian heart and brain depends on pacemaker currents (Ih), which are produced by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Here, we report that the mouse HCN2 channel isoform also a large instantaneous current (Iinst(HCN2)) addition to well characterized, slowly activating Ih. Iinst(HCN2) was specific expression of plasma membrane its amplitude correlated with The two had similar reversal potentials, both were modulated changes...
The sympathetic nervous system increases heart rate by activating β adrenergic receptors and increasing cAMP levels in myocytes the sinoatrial node. molecular basis for this response is not well understood; however, cardiac funny current (If) thought to be among end effectors signaling myocytes. If produced hyperpolarization-activated cyclic nucleotide–sensitive (HCN4) channels, which can potentiated direct binding of a conserved nucleotide domain C terminus channels. regulation node occur...
The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. leading candidates are diastolic depolarization by "funny" current (If) through HCN4 channels (the "Membrane Clock" hypothesis), cardiac Na-Ca exchange (NCX1) response to intracellular Ca cycling "Calcium and a combination two ("Coupled Clock"). To address this controversy, we used Cre/loxP technology generate atrial-specific NCX1 KO mice. protein was undetectable atrial tissue, including SAN. Surface ECG...
AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic exists as αβγ complexes, regulatory γ subunit confers sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 exhibit phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower rate, sarcolemmal hyperpolarization-activated current (I f)...
In skeletal muscle, excitation-contraction (EC) coupling and retrograde signaling are thought to result from direct interactions between the ryanodine receptor (RyR1) alpha(1) subunit of dihydropyridine (alpha(1S)). Previous work has shown that s53 region alpha(1S) (residues 720-765 in II-III loop) regions R10 (1635-2636) R9 (2659-3720) RyR1 involved this signaling. Using yeast two-hybrid system, we here report an interaction sR16 (1837-2168, within R10), whereas no was seen using upstream...
Significance The funny current (I f ) is critical for spontaneous activity in cardiac pacemaker cells; however, its precise role remains enigmatic because it activates mostly outside the physiological voltage range and kinetics are slow relative to cycle. I typically considered as an inward current; we show that persistently active cells. Once opened, small fraction of ion channels conduct do not reclose. Consequently, flows both outward and, paradoxically, conducts a large net charge...
Abnormalities in Ca2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role cardiomyocytes. Alternative splicing of a single triadin gene produces multiple isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by exons 1 to 8. In humans, mutations the that lead reduction Trisk32 levels can cause dysfunction arrhythmias. Decreased also common patients However, mechanisms maintain isoform composition remain...
In mammalian heart and brain, pacemaker currents are produced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, which probably exist as heteromeric assemblies of different subunit isoforms. To investigate the molecular domains that participate in assembly membrane trafficking HCN we have used yeast two-hybrid system, patch clamp electrophysiology, confocal microscopy. We show here N termini HCN1 HCN2 isoforms interacted were essential for expression functional homo- or...
Hyperpolarization-activated HCN pacemaker channels are critical for the generation of spontaneous activity and regulation excitability in heart many types neurons. These produce both a voltage-dependent current (Ih) voltage-independent (Iinst or VIC). In this study, we explored molecular basis current. We found that spHCN isoform, VIC averaged ∼4% maximum conductance could be activated by hyperpolarization. Cyclic AMP increased to ∼8% maximum. HCN2, was ∼2% maximal current, little affected...
A peptide corresponding to residues 681-690 of the II-III loop skeletal muscle dihydropyridine receptor alpha(1) subunit (DHPR, alpha(1S)) has been reported activate ryanodine (RyR1) in vitro. Within this region alpha(1S), a cluster basic residues, Arg(681)-Lys(685), was previously be indispensable for activation RyR1 microsomal preparations and lipid bilayers. We have used an intact alpha(1S) with scrambled sequence (alpha(1S)-scr) test importance motif skeletal-type excitation-contraction...
Sinoatrial node myocytes (SAMs) act as the natural pacemakers of heart, initiating each heart beat by generating spontaneous action potentials (APs). These pacemaker APs reflect coordinated activity numerous membrane currents and intracellular calcium cycling. However precise mechanisms that drive in SAMs remain elusive. Acutely isolated are an essential preparation for experiments to dissect molecular basis cardiac pacemaking. However, indistinct anatomy, complex microdissection, finicky...
Aerobic capacity decreases with age, in part because of an age-dependent decline maximum heart rate (mHR) and a reduction the intrinsic pacemaker activity sinoatrial node heart. Isolated myocytes (SAMs) from aged mice have slower spontaneous action potential (AP) firing rates hyperpolarizing shift voltage dependence activation "funny current," If Cyclic AMP (cAMP) is critical modulator both AP SAMs. Here, we test ability endogenous exogenous cAMP to overcome changes acutely isolated murine...
Significance The pore-forming subunits of ion channels are regulated by auxiliary interacting proteins. Hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) critical determinants electrical excitability in many types cells, including neurons and cardiac pacemaker cells. Here we report the discovery two HCN4 regulatory Despite their homology, proteins—lymphoid-restricted membrane protein (LRMP) inositol trisphosphate receptor-associated guanylate kinase substrate...
The sinoatrial node (SN) generates the heart rate (HR). Its spontaneous activity is regulated by a complex interplay between modulation autonomic nervous system (ANS) and intrinsic factors including ion channels in SN cells. However, systemic regulatory mechanisms are still poorly understood. This study aimed to elucidate sex-specific differences morphology function, particularly focusing on basal HR, expression function of hyperpolarization-activated HCN4 HCN1 mRNA abundance contributing...