David K Jones

University of Michigan | U-M · Department of Pharmacology

This white paper is the outcome of the seventh UC Davis Cardiovascular Research Symposium on Systems Approach to Understanding Cardiovascular Disease and Arrhythmia. This biannual meeting aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2022 Symposium w...

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudd...

Voltage-gated Channel hERG1 conducts rapid delayed rectifier potassium current (IKr) and is critical for repolarization of the human heart. Reduced IKr causes long QT syndrome and increases the risk for cardiac arrhythmia and sudden cardiac death. At least two subunits combine to form functional hERG1 channels, hERG1a and hERG1b. Changes in hERG 1a...

Cardiac myocytes isolated from adult heart tissue have a rod‐like shape with highly organized intracellular structures. Cardiomyocytes derived from human pluripotent stem cells (iPSC‐CMs), on the other hand, exhibit disorganized structure and contractile mechanics, reflecting their pronounced immaturity. These characteristics hamper research using...

hERG1 conducts cardiac IKr and is critical for repolarization of the human heart. Reduced IKr causes long QT syndrome and increases the risk for cardiac arrhythmia and sudden cardiac death. At least two subunits combine to form functional hERG1 channels, hERG1a and hERG1b. Changes in hERG 1a/1b subunit abundance modulates IKr kinetics, magnitude, a...

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudd...

The ERG1 potassium channel, encoded by KCNH2 , has long been associated with cardiac electrical excitability. Yet, a growing body of work suggests that ERG1 mediates physiology throughout the human body, including the brain. ERG1 is a regulator of neuronal excitability, ERG1 variants are associated with neuronal diseases (e.g., epilepsy and schizop...

Cardiac hERG channels comprise at least two subunits, hERG 1a and hERG 1b, and drive cardiac action potential repolarization. hERG 1a subunits contain a cytoplasmic PAS domain that is absent in hERG 1b. The hERG 1a PAS domain regulates voltage sensor domain (VSD) movement, but hERG VSD behavior and its regulation by the hERG 1a PAS domain have not...

Cardiac hERG channels comprise at least two subunits, hERG 1a and hERG 1b, and drive cardiac action potential repolarization. hERG 1a subunits contain a cytoplasmic PAS domain that is absent in hERG 1b. The hERG 1a PAS domain regulates voltage sensor domain (VSD) movement, but hERG VSD behavior and its regulation by the hERG 1a PAS domain have not...

Significance The human ERG (hERG) voltage-gated K ⁺ channel has an important role in heart rhythm, and channel malfunction can result in arrhythmias and sudden death. The Per-Arnt-Sim (PAS) and cyclic nucleotide binding homology (CNBh) domains in hERG influence some of the channel’s unique functional properties. However, the role of these domains i...

Catastrophic arrhythmias and sudden cardiac death can occur with even a small imbalance between inward sodium currents and outward potassium currents, but mechanisms establishing this critical balance are not understood. Here, we show that mRNA transcripts encoding INa and IKr channels (SCN5A and hERG, respectively) are associated in defined comple...

Catastrophic arrhythmias and sudden cardiac death can occur with even a small imbalance between inward sodium currents and outward potassium currents, but mechanisms establishing this critical balance are not understood. Here, we show that mRNA transcripts encoding INa and IKr channels (SCN5A and hERG, respectively) are associated in defined comple...

Reduced levels of hERG protein and the corresponding repolarizing current IKrcan cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. We identified TRIOBP-1, an F-actin binding protein previously associated with actin polymerization, as a putative hERG-interac...

Significance The human ether-à-go-go–related gene (hERG) potassium channel has an important role in controlling heartbeat. Genetic alterations or drug side effects can reduce the amount of current passing through hERG, prolonging action potential duration and causing irregular heartbeat and sudden death. We uncovered a family of hERG modulators, an...

Significance Many ion channels are composed of related but structurally distinct membrane protein subunits, each determining the functional properties of the channel. Although their composition is carefully regulated, the mechanisms underlying their assembly are poorly understood. We show that mRNA transcripts encoding human ether-à-go-go-related g...

The voltage-gated potassium channel hERG (human ether-a-go-go-related gene) is the primary pore-forming subunit of the rapidly activating delayed rectifier potassium channel current (IKr) in the heart. The physiological role of cardiac IKr is the repolarization of the ventricular action potential. Although it is known that certain genetic mutations...

Purpose: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor, with a median survival of less than two years despite maximal therapy. Human ether a gò-gò-related-1 gene (hERG) encodes a voltage-dependent K+ channel found overexpressed in GBM cell lines, and linked to aberrant proliferation in other cancers. We analyzed hERG expre...

The human ether-a-go-go related gene (hERG) encodes two subunits, hERG 1a and hERG 1b, that combine in vivo to conduct the rapid delayed rectifier potassium current (IKr). Reduced IKr slows cardiac action potential (AP) repolarization and is an underlying cause of cardiac arrhythmias associated with long QT syndrome (LQTS). Although the physiologic...

Significance The 1a subunit of the human ether-à-go-go–related gene (hERG) potassium channel is a critical component of cardiac repolarization and the cornerstone of safety screens for new drug development. A second subunit, 1b, coassembles with 1a and modifies channel gating and drug block sensitivity. Adoption of 1a/1b heteromers as a model of na...

Voltage-gated sodium (NaV) channels generate the upstroke and mediate duration of the ventricular action potential, thus they play a critical role in mediating cardiac excitability. Cardiac ischemia triggers extracellular pH to drop as low as pH 6.0, within just 10 min of its onset. Heightened proton concentrations reduce sodium conductance and alt...

Low pH depolarizes the voltage-dependence of cardiac voltage-gated sodium (NaV1.5) channel activation and fast inactivation and destabilizes the fast-inactivated state. The molecular basis for these changes in protein behavior has not been reported. We hypothesized that changes in the kinetics of voltage sensor movement may destabilize the fast-ina...

Protons impart isoform-specific modulation of inactivation in neuronal, skeletal muscle, and cardiac voltage-gated sodium (NaV) channels. Although the structural basis of proton block in NaV channels has been well described, the amino acid residues responsible for the changes in NaV kinetics during extracellular acidosis are as yet unknown. We expr...

Low pH reduces single channel conductance and destabilizes the fast-inactivated state of the cardiac voltage-gated sodium channel (NaV1.5) by increasing both window and persistent currents (Jones et al., 2011, Biophys. J. 101(7)). Since fast inactivation is tightly coupled to NaV channel voltage sensor activation, we hypothesized that alterations i...

Low pH depolarizes the voltage dependence of voltage-gated sodium (Na(V)) channel activation and fast inactivation. A complete description of Na(V) channel proton modulation, however, has not been reported. The majority of Na(V) channel proton modulation studies have been completed in intact tissue. Additionally, several Na(V) channel isoforms are...

Tetrodotoxin (TTX) is a potent toxin that specifically binds to voltage-gated sodium channels (NaV). TTX binding physically blocks the flow of sodium ions through NaV, thereby preventing action potential generation and propagation. TTX has different binding affinities for different NaV isoforms. These differences are imparted by amino acid substitu...

Alterations in the function of the cardiac voltage-gated sodium channel (NaV1.5) are a known cause of cardiac disease and arrhythmia. Elevated concentrations of protons decrease conductance and depolarize the voltage dependence of activation and steady-state fast inactivation (SSFI) of NaV1.5 channels (Zhang & Siegelbaum, 1991, Khan et al., 2006)....

Tetrodotoxin (TTX) is a potent toxin that specifically binds to voltage gated sodium channels (NaV). TTX binding physically blocks the flow of sodium ions through NaV, thereby preventing action potential generation and propagation. Populations of the garter snake, Thamnophis sirtalis, have evolved TTX resistance by substituting amino acid residues...

The activity of voltage-gated sodium channels contributes to onset and duration of the cardiac action potential through an intricate balance with the activity of other ion channels. Activation of sodium channels leads to membrane depolarization and Phase 0 of the cardiac action potential. Sodium channel fast inactivation contributes to Phase 1, the...