A5030095899- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Neuroscience of respiration and sleep
- Ion Channels and Receptors
- Epilepsy research and treatment
- Cardiac electrophysiology and arrhythmias
- Adenosine and Purinergic Signaling
- Receptor Mechanisms and Signaling
- Neurobiology and Insect Physiology Research
- Sleep and Wakefulness Research
- Phytochemicals and Antioxidant Activities
- Neuroscience and Neural Engineering
- Pharmacological Receptor Mechanisms and Effects
- Genetics and Neurodevelopmental Disorders
- Heme Oxygenase-1 and Carbon Monoxide
- Postharvest Quality and Shelf Life Management
- Neurogenesis and neuroplasticity mechanisms
- Pharmacological Effects and Toxicity Studies
- Cannabis and Cannabinoid Research
- Hemoglobin structure and function
- Nicotinic Acetylcholine Receptors Study
- Neuroendocrine regulation and behavior
- Genetic and Kidney Cyst Diseases
- Neurological disorders and treatments
- Phosphodiesterase function and regulation
Florey Institute of Neuroscience and Mental Health
2014-2024
The University of Melbourne
2015-2024
Royal Children's Hospital
2016
University of Washington
2016
Austin Health
2016
University of Cape Town
2016
University of Leeds
2003-2012
Leeds General Infirmary
2008-2010
AstraZeneca (United Kingdom)
2010
Mutations in KCNT1 have been implicated autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study epileptic encephalopathies identified an additional de novo mutation 1 proband EIMFS. We aim to investigate the electrophysiological pharmacological characteristics hKCNT1 mutations examine developmental expression levels.Here we use Xenopus laevis oocyte-based automated 2-electrode voltage...
We report 2 patients with drug‐resistant epilepsy caused by KCNT1 mutations who were treated quinidine. Both manifested gain of function in vitro, showing increased current that was reduced One, had infancy migrating focal seizures, 80% reduction seizure frequency as recorded diaries, and partially validated objective evaluation on EEG. The other, a novel phenotype, severe nocturnal secondary generalized seizures starting early childhood developmental regression, did not improve. Although...
The ionotropic ATP receptor subunits P2X<sub>1–6</sub> receptors play important roles in synaptic transmission, yet the P2X<sub>7</sub>receptor has been reported as absent from neurons normal adult brain. Here we use RT-PCR to demonstrate that transcripts for P2X<sub>7</sub> are present extracts medulla oblongata, spinal cord, and nodose ganglion. Using <i>in situ</i> hybridization mRNA encoding, was detected numerous throughout oblongata cord. Localizing protein with immunohistochemistry...
Abstract Although originally cloned from rat brain, the P2X 7 receptor has only recently been localized in neurones, and functional responses mediated by these neuronal receptors (P2X R) are largely unknown. Here we studied effect of R activation on release neurotransmitters superfused hippocampal slices. ATP (1–30 m ) other analogues elicited concentration‐dependent [ 3 H]GABA outflow, with following rank order potency: benzoylbenzoylATP (BzATP) > ADP. PPADS, non‐selective P2‐receptor...
Transient receptor potential melastatin (TRPM)3 is a calcium-permeable ion channel activated by the neurosteroid pregnenolone sulfate and positively coupled to insulin secretion in beta cells. Although vascular TRPM3 mRNA has been reported, there no knowledge of protein or its regulation function cardiovascular system.To determine relevance biology.TRPM3 expression was detected at levels contractile proliferating smooth muscle Calcium entry evoked sphingosine suppressed blocking antibody...
Significance Spider venom is a rich source of peptides, many targeting ion channels. We assessed peptide, Hm1a, as potential targeted therapy for Dravet syndrome, the genetic epilepsy linked to mutation in gene encoding sodium channel alpha subunit Na V 1.1. Cell-based assays showed Hm1a was selective hNa 1.1 over other and potassium Utilizing mouse model restored inhibitory neuron function significantly reduced seizures mortality heterozygote mice. Evidence from structure modeling suggest...
Oxidative stress induces neuronal apoptosis and is implicated in cerebral ischemia, head trauma, age-related neurodegenerative diseases. An early step this process the loss of intracellular K+ via channels, evidence indicates that Kv2.1 particular importance regard, being rapidly inserted into plasma membrane response to apoptotic stimuli. additional feature oxidative up-regulation inducible enzyme heme oxygenase-1 (HO-1), which catabolizes generate biliverdin, Fe2+, carbon monoxide (CO). CO...
Clinical reports describe life-threatening cardiac arrhythmias after environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies disruption of repolarization and prolongation the QT interval, yet mechanisms underlying CO-induced are unknown.
To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization observed clinical improvement with fever.We analyzed clinical, electroclinical, neuroimaging data for 20 patients MEAK recurrent KCNC1 p.R320H mutation. In vitro studies were conducted using whole cell patch-clamp explore biophysical properties wild-type mutant KV 3.1 channels.Symptoms began at between 3 15 years age...
Stromal interaction molecule 1 (STIM1) is a predicted single membrane-spanning protein involved in store-operated calcium entry and interacting with ion channels including TRPC1. Here, we focus on endogenous STIM1 of modulated vascular smooth muscle cells, which exhibited nonselective cationic current response to store depletion despite strong buffering intracellular at the physiological concentration. mRNA were detected suppressed by specific short interfering RNA. Calcium evoked was...
The aim of this study was to generate new insight into chemical regulation transient receptor potential (TRP) channels with relevance glucose homeostasis and the metabolic syndrome. Human TRP melastatin 2 (TRPM2), TRPM3, canonical 5 (TRPC5) were conditionally overexpressed in human embryonic kidney 293 cells studied by using calcium-measurement patch-clamp techniques. Rosiglitazone other peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists investigated. TRPM2 unaffected...
We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group epilepsies.The was designed using molecular inversion probe (MIP) capture technology and sequenced massively parallel Illumina sequencing.We demonstrated proof principle that mutations can be detected in 4 previously genotyped epilepsy cases. searched both germline somatic 251 patients with unsolved sporadic or familial identified 11 novel very rare missense variants 5...
Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility multiple sclerosis (MS). In this study, we set out evaluate whether rare coding of major effect could also be identified these receptors. Sequencing analysis 193 MS patients 100 controls led identification a three variant haplotype (P2RX7 rs140915863:C>T [p.T205M], rs201921967:A>G [p.N361S], rs765866317:G>A [p.G135S]) segregating with disease multi-incident family six members diagnosed...
We have studied the effect of 8-bromo-cyclic GMP (8-Br-cGMP) on cloned cardiac l-type calcium channel currents to determine site and mechanism action underlying functional effect. Rabbit α1C subunit, in presence or absence β1 subunit (rabbit skeletal muscle) β2 (rat cardiac/brain), was expressed Xenopus oocytes, two-electrode voltage-clamp recordings were made 2 3 days later. Application 8-Br-cGMP caused decreases cells expressing whether not a β co-expressed. No inhibition by observed...
Fast inhibition in the nervous system is commonly mediated by GABA(A) receptors comprised of 2alpha/2beta/1gamma subunits. In contrast, GABA(C) containing only rho subunits (rho1-rho3) have been predominantly detected retina. However, here using reverse transcription-PCR and situ hybridization we show that mRNA encoding rho1 subunit highly expressed brainstem neurons. Immunohistochemistry localized to neurons at light electron microscopic levels, where it was synaptic junctions. Application...
The accessory β subunits of voltage-dependent potassium (Kv) channels form tetramers arranged with 4-fold rotational symmetry like the membrane-integral and pore-forming α (Gulbis, J. M., Mann, S., MacKinnon, R. (1999) <i>Cell.</i> 90, 943–952). crystal structure Kvβ2 subunit shows that Kvβ are oxidoreductase enzymes containing an active site composed conserved catalytic residues, a nicotinamide (NADPH)-cofactor, substrate binding site. Also, N-terminal inactivating domain Kvβ1.1 (Rettig,...
Homeostatic maintenance of widespread functions is critically dependent on the activity sympathetic nervous system. This generated by CNS acting sole output cells in spinal cord, preganglionic neurons (SPNs). SPNs are subject to control from both supraspinal and inputs that exert effects through activation direct or indirect pathways. A high proportion attributable interneurons a number locations. However, little known about different groups with respect their neurochemistry function. In...
Objective— To determine whether calcium-permeable channels are targets for the oxidized phospholipids: 1-palmitoyl-2-glutaroyl-phosphatidylcholine (PGPC) and 1-palmitoyl-2-oxovaleroyl-phosphatidylcholine (POVPC). Methods Results— Oxidized phospholipids key factors in inflammation associated diseases, including atherosclerosis; however, initial reception mechanisms cellular responses to poorly understood. Low micromolar concentrations of PGPC POVPC evoked increases intracellular calcium human...
Isoform-specific ion channel blockers are useful for target validation in drug discovery and can provide the basis new therapeutic agents aid determination of physiological functions channels. The aim this study was to generate a specific blocker human TRPM3 channels as tool help investigations member TRP cationic family.A polyclonal antibody (TM3E3) made conserved peptide third extracellular (E3) loop tested binding functional effect. Studies activity were by whole-cell planar patch-clamp...