A5025356114- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neural Engineering
- Neuroscience and Neuropharmacology Research
- Epilepsy research and treatment
- Memory and Neural Mechanisms
- Cardiac Arrhythmias and Treatments
- Cellular transport and secretion
- Genetics and Neurodevelopmental Disorders
- ECG Monitoring and Analysis
- Electrochemical Analysis and Applications
- Cardiomyopathy and Myosin Studies
- Receptor Mechanisms and Signaling
Xenon Pharmaceuticals (Canada)
2022-2024
Canada's Michael Smith Genome Sciences Centre
2021
University of British Columbia
2019-2021
Simon Fraser University
2011-2020
Michael Smith Health Research BC
2019
University of Leicester
2010
Human ether-à-go-go-related gene (hERG) K(+) channels have a critical role in cardiac repolarization. hERG close (deactivate) very slowly, and this is vital for regulating the time course amplitude of repolarizing current during action potential. Accelerated deactivation one mechanism by which inherited mutations cause long QT syndrome potentially lethal arrhythmias. highly dependent upon an intact EAG domain (the first 135 amino acids N terminus). Importantly, deletion residues 2-26...
Voltage-gated sodium channel (NaV) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing reduce excitability in the brain. However, all currently available NaV-targeting antiseizure medications nonselectively inhibit brain channels NaV1.1, NaV1.2, and NaV1.6, which potentially limits efficacy therapeutic safety margins these drugs. Here, we report on XPC-7724 XPC-5462, represent a new class...
Palmitoylation is a reversible post-translational lipid modification that facilitates vesicular transport and subcellular localization of modified proteins. This process catalyzed by ZDHHC enzymes are implicated in several neurological neurodevelopmental disorders. Loss-of-function mutations ZDHHC9 have been identified patients with X-linked intellectual disability (XLID) associated increased epilepsy risk. Loss Zdhhc9 function hippocampal cultures leads to shorter dendritic arbors fewer...
Abstract K v 1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking subunits ( Kcna1 −/− ) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in mice resemble those well-characterized models of temporal lobe epilepsy known to involve limbic brain regions result enhanced cFos expression death the amygdala. Yet, functional alterations leading amygdala hyperexcitability have not been identified. In this...
hERG channels underlie the delayed-rectifier K+ channel current (IKr), which is crucial for membrane repolarization and therefore termination of cardiac action potential. display unusually slow deactivation gating, contributes to a resurgent upon may protect against post-depolarization-induced arrhythmias. also exhibit robust mode shift behavior, reflects energetic separation activation pathways due voltage sensor relaxation into stable activated state. The mechanism unknown likely...
The hERG channel is a key player in repolarization of the cardiac action potential. Pharmacological blockade channels depletes reserve, increasing risk arrhythmias. promiscuous nature drug interactions with presents therapeutic challenge for design and development. Despite considerable effort, mechanisms binding remain incompletely understood. One proposed mechanism that high-affinity preferentially occurs when are inactivated state. However, this has been difficult to test, since...
Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of nine human channel subtypes, Nav1.1, Nav1.2 Nav1.6 prominently expressed adult central nervous system (CNS). All three these subtypes sensitive to block by neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all subtypes. In present study we have used determine fractional Nav required impair potential firing pyramidal neurons reduce network seizure-like...
Abstract Sodium channel inhibitors are used to treat neurological disorders of hyperexcitability. However, all currently available sodium targeting anti-seizure medications non-selective among the Na V isoforms which potentially limits efficacy and therapeutic safety margins. XPC-7724 XPC-5462 represent a new class small molecule compounds. These compounds target inhibition 1.6 1.2 channels in excitatory pyramidal neurons possess molecular selectivity >100 fold against 1.1 that dominant...
Abstract Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of different channel subtypes, Nav1.1, Nav1.2 Nav1.6 prominently expressed adult central nervous system (CNS). All three these subtypes sensitive to block by neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all subtypes. In present study we have used determine fractional Nav required impair potential firing pyramidal neurons reduce network...