ORCID Profile
0000-0003-2846-052X
Current Organisations
University of Queensland
,
University of New South Wales
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Animal Physiology - Biophysics | Protein Trafficking | Biochemistry and cell biology | Biochemistry and Cell Biology | Signal transduction | Receptors and membrane biology | Neurosciences | Central Nervous System | Receptors and Membrane Biology | Cell Neurochemistry
ANZSRC Socio-Economic Objective (SEO)
Nervous System and Disorders | Mental Health | Expanding Knowledge in the Biological Sciences |
Related Links
Publications
Structure-Function Analysis of the GlyR α2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function.
Publisher: Frontiers Media SA
Date: 23-05-2017
A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition
Publisher: Society for Neuroscience
Date: 30-04-2020
Anti-seizure mechanisms of midazolam and valproate at the β2(L51M) variant of the GABAA receptor
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.NEUROPHARM.2022.109295
Abstract: Genetic sequencing is identifying an expanding number of variants of GABA A receptors associated with human epilepsies. We identified a new de novo variant of the β2 subunit (β2L51M) of the inhibitory GABA A receptor associated with seizures. Our analysis determined the pathogenicity of the variant and the effects of anti-seizure medications. Our data demonstrates that the variant reduced cell surface trafficking and peak GABA-gated currents. Synaptic currents mediated by variant-containing receptors decayed faster than wild-type and single receptor currents showed that the variant shortened the duration of receptor activity by decreasing receptor open times. We tested the effects of the anti-seizure medications, midazolam, carbamazepine and valproate and found that all three enhance variant receptor surface expression. Additionally, midazolam restored receptor function by increasing single receptor active periods and synaptic current decay times towards wild-type levels. By contrast, valproate increased synaptic peak currents, event frequency and promoted synaptic bursting. Our study identifies a new disease-causing variant to the GABA A receptor, profiles its pathogenic effects and demonstrates how anti-seizure drugs correct its functional deficits.
Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a
Publisher: Proceedings of the National Academy of Sciences
Date: 20-03-2017
Abstract: Six million people die each year from stroke, and 5 million survivors are left with a permanent disability. Moreover, the neuronal damage caused by stroke often triggers a progressive decline in cognitive function that doubles the risk of dementia for stroke survivors. Despite this massive global disease burden, there are no approved drugs for treating the neuronal injury caused to the brain by the oxygen deprivation occurring during an ischemic stroke. The precipitous drop in brain pH resulting from stroke activates acid-sensing ion channel 1a. We show that inhibition of these channels using a “double-knot” spider venom peptide massively attenuates brain damage after stroke and improves behavioral outcomes, even when the peptide is administered 8 h after stroke onset.
Ivermectin-activated, cation-permeable glycine receptors for the chemogenetic control of neuronal excitation
Publisher: American Chemical Society (ACS)
Date: 27-09-2016
DOI: 10.1021/ACSCHEMNEURO.6B00168
Abstract: The ability to control neuronal activation is rapidly advancing our understanding of brain function and is widely viewed as having eventual therapeutic application. Although several highly effective optogenetic, optochemical genetic, and chemogenetic techniques have been developed for this purpose, new approaches may provide better solutions for addressing particular questions and would increase the number of neuronal populations that can be controlled independently. An early chemogenetic neuronal silencing method employed a glutamate receptor Cl
Taurine Is a Potent Activator of Extrasynaptic GABAAReceptors in the Thalamus
Publisher: Society for Neuroscience
Date: 02-01-2008
DOI: 10.1523/JNEUROSCI.3996-07.2008
Abstract: Taurine is one of the most abundant free amino acids in the brain. In a number of studies, taurine has been reported to activate glycine receptors (Gly-Rs) at moderate concentrations (≥100 μ m ), and to be a weak agonist at GABA A receptors (GABA A -Rs), which are usually activated at high concentrations (≥1 m m ). In this study, we show that taurine reduced the excitability of thalamocortical relay neurons and activated both extrasynaptic GABA A -Rs and Gly-Rs in neurons in the mouse ventrobasal (VB) thalamus. Low concentrations of taurine (10–100 μ m ) decreased neuronal input resistance and firing frequency, and elicited a steady outward current under voltage cl , but had no effects on fast inhibitory synaptic currents. Currents elicited by 50 μ m taurine were abolished by gabazine, insensitive to midazolam, and partially blocked by 20 μ m Zn 2+ , consistent with the pharmacological properties of extrasynaptic GABA A -Rs (α4β2δ subtype) involved in tonic inhibition in the thalamus. Tonic inhibition was enhanced by an inhibitor of taurine transport, suggesting that taurine can act as an endogenous activator of these receptors. Taurine-evoked currents were absent in relay neurons from GABA A -R α4 subunit knock-out mice. The litude of the taurine current was larger in neurons from adult mice than juvenile mice. Taurine was a more potent agonist at recombinant α4β2δ GABA A -Rs than at α1β2γ2 GABA A -Rs. We conclude that physiological concentrations of taurine can inhibit VB neurons via activation of extrasynaptic GABA A -Rs and that taurine may function as an endogenous regulator of excitability and network activity in the thalamus.
M2 pore mutations convert the glycine receptor channel from being anion- to cation-selective
Publisher: Elsevier BV
Date: 07-2000
Gamma 1-containing GABA-A receptors cluster at synapses where they mediate slower synaptic currents than gamma 2-containing GABA-A receptors
Publisher: Frontiers Media SA
Date: 08-06-2017
SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAA Receptor γ2 Subunit
Publisher: Frontiers Media SA
Date: 23-03-2018
Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses
Publisher: Frontiers Media SA
Date: 30-04-2014
Probing the Structural Mechanism of Partial Agonism in Glycine Receptors Using the Fluorescent Artificial Amino Acid, ANAP
Publisher: American Chemical Society (ACS)
Date: 02-02-2017
DOI: 10.1021/ACSCHEMBIO.6B00926
Abstract: The efficacy of an agonist at a pentameric ligand-gated ion channel is determined by the rate at which it induces a conformational change from the resting closed state to a preopen ("flip") state. If the ability of an agonist to promote this isomerization is sufficiently low, then it becomes a partial agonist. As partial agonists at pentameric ligand-gated ion channels show considerable promise as therapeutics, understanding the structural basis of the resting-flip-state isomerization may provide insight into therapeutic design. Accordingly, we sought to identify structural correlates of the resting-flip conformational change in the glycine receptor chloride channel. We used nonsense suppression to introduce the small, fluorescent amino acid, 3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (ANAP), into specific sites in the extracellular and transmembrane domains. Then, under voltage-cl conditions in Xenopus oocytes, we simultaneously quantified current and fluorescence responses induced by structurally similar agonists with high, medium, and low efficacies (glycine, β-alanine, and taurine, respectively). Analyzing results from nine ANAP-incorporated sites, we show that glycine receptor activation by agonists with graded efficacies manifests structurally as correspondingly graded movements of the β1-β2 loop, the β8-β9 loop, and the Cys-loop from the extracellular domain and the TM2-TM3 linker in the transmembrane domain. We infer that the resting-flip transition involves an efficacy-dependent molecular reorganization at the extracellular-transmembrane domain interface that primes receptors for efficacious opening.
Cation-selective Mutations in the M2 Domain of the Inhibitory Glycine Receptor Channel Reveal Determinants of Ion-Charge Selectivity
Publisher: Rockefeller University Press
Date: 15-04-2002
DOI: 10.1085/JGP.20028552
Abstract: Ligand-gated ion channel receptors mediate neuronal inhibition or excitation depending on their ion charge selectivity. An investigation into the determinants of ion charge selectivity of the anion-selective α1 homomeric glycine receptor (α1 glycine receptor [GlyR]) was undertaken using point mutations to residues lining the extra- and intracellular ends of the ion channel. Five mutant GlyRs were studied. A single substitution at the intracellular mouth of the channel (A-1′E GlyR) was sufficient to convert the channels to select cations over anions with PCl/PNa = 0.34. This result delimits the selectivity filter and provides evidence that electrostatic interactions between permeating ions and pore residues are a critical factor in ion charge selectivity. The P-2′Δ mutant GlyR retained its anion selectivity (PCl/PNa = 3.81), but it was much reduced compared with the wild-type (WT) GlyR (PCl/PNa = 27.9). When the A-1′E and the P-2′Δ mutations were combined (selectivity double mutant [SDM] GlyR), the relative cation permeability was enhanced (PCl/PNa = 0.13). The SDM GlyR was also Ca2+ permeable (PCa/PNa = 0.29). Neutralizing the extracellular mouth of the SDM GlyR ion channel (SDM+R19′A GlyR) produced a more Ca2+-permeable channel (PCa/PNa = 0.73), without drastically altering monovalent charge selectivity (PCl/PNa = 0.23). The SDM+R19′E GlyR, which introduces a negatively charged ring at the extracellular mouth of the channel, further enhanced Ca2+ permeability (PCa/PNa = 0.92), with little effect on monovalent selectivity (PCl/PNa = 0.19). Estimates of the minimum pore diameter of the A-1′E, SDM, SDM+R19′A, and SDM+R19′E GlyRs revealed that these pores are larger than the α1 GlyR, with the SDM-based GlyRs being comparable in diameter to the cation-selective nicotinic acetylcholine receptors. This result provides evidence that the diameter of the ion channel is also an important factor in ion charge selectivity.
The pre‐M1 segment of the α1 subunit is a transduction element in the activation of the GABAA receptor
Publisher: Wiley
Date: 08-08-2006
Single Channel Analysis of Conductance and Rectification in Cation-selective, Mutant Glycine Receptor Channels
Publisher: Rockefeller University Press
Date: 15-04-2002
DOI: 10.1085/JGP.20028553
Abstract: Members of the ligand-gated ion channel superfamily mediate fast synaptic transmission in the nervous system. In this study, we investigate the molecular determinants and mechanisms of ion permeation and ion charge selectivity in this family of channels by characterizing the single channel conductance and rectification of α1 homomeric human glycine receptor channels (GlyRs) containing pore mutations that impart cation selectivity. The A-1'E mutant GlyR and the selectivity double mutant ([SDM], A-1'E, P-2'Δ) GlyR, had mean inward chord conductances (at −60 mV) of 7 pS and mean outward conductances of 11 and 12 pS (60 mV), respectively. This indicates that the mutations have not simply reduced anion permeability, but have replaced the previous anion conductance with a cation one. An additional mutation to neutralize the ring of positive charge at the extracellular mouth of the channel (SDM+R19'A GlyR) made the conductance–voltage relationship linear (14 pS at both 60 and −60 mV). When this external charged ring was made negative (SDM+R19'E GlyR), the inward conductance was further increased (to 22 pS) and now became sensitive to external alent cations (being 32 pS in their absence). The effects of the mutations to the external ring of charge on conductance and rectification could be fit to a model where only the main external energy barrier height for permeation was changed. Mean outward conductances in the SDM+R19'A and SDM+R19'E GlyRs were increased when internal alent cations were absent, consistent with the intracellular end of the pore being flanked by fixed negative charges. This supports our hypothesis that the ion charge selectivity mutations have inverted the electrostatic profile of the pore by introducing a negatively charged ring at the putative selectivity filter. These results also further confirm the role of external pore vestibule electrostatics in determining the conductance and rectification properties of the ligand-gated ion channels.
Physiological and pharmacological properties of inhibitory postsynaptic currents mediated by α5β1γ2, α5β2γ2 and α5β3γ2 GABA A receptors
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.NEUROPHARM.2017.07.027
Abstract: α5-containing GABA
Ligand-gated ion channels: mechanisms underlying ion selectivity
Publisher: Elsevier BV
Date: 10-2004
Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity
Publisher: Wiley
Date: 11-05-2015
DOI: 10.1111/BPH.13142
The activation mechanism of α1β2γ2S and α3β3γ2S GABAA receptors
Publisher: Rockefeller University Press
Date: 28-12-2009
Abstract: The α1β2γ2 and α3β3γ2 are two isoforms of γ-aminobutyric acid type A (GABAA) receptor that are widely distributed in the brain. Both are found at synapses, for ex le in the thalamus, where they mediate distinctly different inhibitory postsynaptic current profiles, particularly with respect to decay time. The two isoforms were expressed in HEK293 cells, and single-channel activity was recorded from outside-out patches. The kinetic characteristics of both isoforms were investigated by analyzing single-channel currents over a wide range of GABA concentrations. α1β2γ2 channels exhibited briefer active periods than α3β3γ2 channels over the entire range of agonist concentrations and had lower intraburst open probabilities at subsaturating concentrations. Activation mechanisms were constructed by fitting postulated schemes to data recorded at saturating and subsaturating GABA concentrations simultaneously. Reaction mechanisms were ranked according to log-likelihood values and how accurately they simulated ensemble currents. The highest ranked mechanism for both channels consisted of two sequential binding steps, followed by three conducting and three nonconducting configurations. The equilibrium dissociation constant for GABA at α3β3γ2 channels was ∼2.6 µM compared with ∼19 µM for α1β2γ2 channels, suggesting that GABA binds to the α3β3γ2 channels with higher affinity. A notable feature of the mechanism was that two consecutive doubly liganded shut states preceded all three open configurations. The lifetime of the third shut state was briefer for the α3β3γ2 channels. The longer active periods, higher affinity, and preference for conducting states are consistent with the slower decay of inhibitory currents at synapses that contain α3β3γ2 channels. The reaction mechanism we describe here may also be appropriate for the analysis of other types of GABAA receptors and provides a framework for rational investigation of the kinetic effects of a variety of therapeutic agents that activate or modulate GABAA receptors and hence influence synaptic and extrasynaptic inhibition in the central nervous system.
Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit
Publisher: Elsevier BV
Date: 07-2021
Correlating structural and energetic changes in glycine receptor activation
Publisher: Elsevier BV
Date: 02-2015
A pain-causing and paralytic ant venom glycopeptide
Publisher: Elsevier BV
Date: 10-2021
The Free Zinc Concentration in the Synaptic Cleft of Artificial Glycinergic Synapses Rises to At least 1 μM
Publisher: Frontiers Media SA
Date: 22-09-2016
The effects of insecticides on two splice variants of the glutamate‐gated chloride channel receptor of the major malaria vector, Anopheles gambiae
Publisher: Wiley
Date: 31-10-2019
DOI: 10.1111/BPH.14855
An outline of desensitization in pentameric ligand-gated ion channel receptors
Publisher: Springer Science and Business Media LLC
Date: 31-08-2012
DOI: 10.1007/S00018-012-1133-Z
Abstract: Pentameric ligand-gated ion channel (pLGIC) receptors exhibit desensitization, the progressive reduction in ionic flux in the prolonged presence of agonist. Despite its pathophysiological importance and the fact that it was first described over half a century ago, surprisingly little is known about the structural basis of desensitization in this receptor family. Here, we explain how desensitization is defined using functional criteria. We then review recent progress into reconciling the structural and functional basis of this phenomenon. The extracellular-transmembrane domain interface is a key locus. Activation is well known to involve conformational changes at this interface, and several lines of evidence suggest that desensitization involves a distinct conformational change here that is incompatible with activation. However, major questions remain unresolved, including the structural basis of the desensitization-induced agonist affinity increase and the mechanism of pore closure during desensitization.
GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance
Publisher: Public Library of Science (PLoS)
Date: 29-01-2019
Proteostasis Regulators Restore Function of Epilepsy-Associated GABAA Receptors
Publisher: Elsevier BV
Date: 2021
Collisions of antiprotons with excited positronium atoms
Publisher: American Physical Society (APS)
Date: 06-12-2021
The contribution of proline 250 (P-2′) to pore diameter and ion selectivity in the human glycine receptor channel
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.NEULET.2003.08.005
Abstract: The glycine receptor-channel (GlyR) mediates neuronal inhibition by selectively allowing the passage of Cl(-) ions through its channel. The pore region for ion selectivity is localised to the constricted internal end of the M2 transmembrane domain. This paper investigates the contribution of the P-2' residue in determining pore diameter and ion charge selectivity of the GlyR. The deletion of this proline has been shown to decrease the anion/cation permeability ratio, with P(Cl)/P(Na) decreasing from approximately 27 to approximately 4. We show that the P-2' deletion by itself produces a GlyR with a larger pore diameter ( approximately 0.69 nm) than the wild type value ( approximately 0.54 nm). This confirms that the P-2' residue reduces pore size, which suggests that, in addition to electrostatic effects, pore size also contributes to ion-charge selectivity.
Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus
Publisher: Public Library of Science (PLoS)
Date: 02-10-2017
GABAa receptor α and γ subunits shape synaptic currents via different mechanisms
Publisher: Elsevier BV
Date: 02-2014
Effects of GluN2A and GluN2B gain-of-function epilepsy mutations on synaptic currents mediated by diheteromeric and triheteromeric NMDA receptors.
Publisher: Elsevier BV
Date: 07-2020
Identification of Molluscan Nicotinic Acetylcholine Receptor (nAChR) Subunits Involved in Formation of Cation- and Anion-Selective nAChRs
Publisher: Society for Neuroscience
Date: 16-11-2005
DOI: 10.1523/JNEUROSCI.2015-05.2005
Abstract: Acetylcholine (ACh) is a neurotransmitter commonly found in all animal species. It was shown to mediate fast excitatory and inhibitory neurotransmission in the molluscan CNS. Since early intracellular recordings, it was shown that the receptors mediating these currents belong to the family of neuronal nicotinic acetylcholine receptors and that they can be distinguished on the basis of their pharmacology. We previously identified 12 Lymnaea cDNAs that were predicted to encode ion channel subunits of the family of the neuronal nicotinic acetylcholine receptors. These Lymnaea nAChRs can be sub ided in groups according to the residues supposedly contributing to the selectivity of ion conductance. Functional analysis in Xenopus oocytes revealed that two types of subunits with predicted distinct ion selectivities form homopentameric nicotinic ACh receptor (nAChR) subtypes conducting either cations or anions. Phylogenetic analysis of the nAChR gene sequences suggests that molluscan anionic nAChRs probably evolved from cationic ancestors through amino acid substitutions in the ion channel pore, a mechanism different from acetylcholine-gated channels in other invertebrates.
Inhibitory synapse deficits caused by familial α1 GABAA receptor mutations in epilepsy
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.NBD.2017.08.020
Abstract: Epilepsy is a spectrum of neurological disorders with many causal factors. The GABA type-A receptor (GABA
Measurement of the limiting equivalent conductivities and mobilities of the most prevalent ionic species of EGTA (EGTA(2-) and EGTA(3-)) for use in electrophysiological experiments
Publisher: Elsevier BV
Date: 07-1999
DOI: 10.1016/S0165-0270(99)00036-9
Abstract: In many experimental biological situations, chelating agents like EGTA (ethylene glycol-bis-(beta-amino-ethyl ether) N,N,N',N'-tetra-acetic acid) are commonly used to control or suppress the concentration of alent ions like Ca2+. The evaluation of liquid junction potentials in electrophysiological measurements, and particularly in patch-cl situations, requires information about the ions within the solution. Where there is a significant concentration of EGTA present, it is necessary to know the values of the relative mobility of at least the most predominant ionic species of EGTA in order to complete these calculations. EGTA, with four negative charges with different pKas, can therefore exist as four differently charged ions in solution (EGTA-, EGTA2-, EGTA3- and EGTA4-) or as uncharged, although between pH 5.5 and 8 it is almost exclusively EGTA2-. We have measured limiting equivalent conductivities of the most common ionic forms of EGTA (EGTA2- and EGTA3-) encountered at physiological pHs. These were 35.9 +/- 0.7 and 56 +/- 2.5 S cm2 equiv(-1) respectively. Their mobilities relative to K+ were 0.24 +/- 0.01 for EGTA2- and 0.25 +/- 0.01 for EGTA3-. Thus for typical electrophysiological solutions, the contribution of EGTA to the liquid junction potential should be small (e.g. approximately 0.4 mV).
Erythromelalgia caused by the missense mutation p.Arg220Pro in an alternatively spliced exon of SCN9A (NaV1.7)
Publisher: Oxford University Press (OUP)
Date: 18-09-2023
DOI: 10.1093/HMG/DDAD152
New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms
Publisher: Elsevier BV
Date: 11-2013
GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms
Publisher: Wiley
Date: 17-10-2023
DOI: 10.1111/EPI.17776
Functional reconstitution of glycinergic synapses incorporating defined glycine receptor subunit combinations
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.NEUROPHARM.2014.10.026
Abstract: Glycine receptor (GlyR) chloride channels mediate fast inhibitory neurotransmission in the spinal cord and brainstem. Four GlyR subunits (α1-3, β) have been identified in humans, and their differential anatomical distributions underlie a ersity of synaptic isoforms with unique physiological and pharmacological properties. To improve our understanding of these properties, we induced the formation of recombinant synapses between cultured spinal neurons and HEK293 cells expressing GlyR subunits of interest plus the synapse-promoting molecule, neuroligin-2A. In the heterosynapses thus formed, recombinant α1β and α3β GlyRs mediated fast decaying inhibitory postsynaptic currents (IPSCs) whereas α2β GlyRs mediated slow decaying IPSCs. These results are consistent with the fragmentary information available from native synapses and single channel kinetic studies. As β subunit incorporation is considered essential for localizing GlyRs at the synapse, we were surprised that α1-3 homomers supported robust IPSCs with β subunit incorporation accelerating IPSC rise and decay times in α2β and α3β heteromers only. Finally, heterosynapses incorporating α1(D80A)β and α1(A52S)β GlyRs exhibited accelerated IPSC decay rates closely resembling those recorded in native synapses from mutant mice homozygous for these mutations, providing an additional validation of our technique. Glycinergic heterosynapses should prove useful for evaluating the effects of drugs, hereditary disease mutations or other interventions on defined GlyR subunit combinations under realistic synaptic activation conditions.
Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity
Publisher: Oxford University Press (OUP)
Date: 30-08-2023
Abstract: Genetic variants associated with developmental and epileptic encephalopathies have been identified in the GABRB3 gene that encodes the β3 subunit of GABAA receptors. Typically, variants alter receptor sensitivity to GABA resulting in either gain- or loss-of-function, which correlates with patient phenotypes. However, it is unclear how another important receptor property, desensitization, contributes to the greater clinical severity of gain-of-function variants. Desensitization properties of 20 gain-of-function GABRB3 variant receptors were evaluated using two-electrode voltage-cl electrophysiology. The parameters measured included current decay rates and steady-state currents. Selected variants with increased or reduced desensitization were also evaluated using whole-cell electrophysiology in transfected mammalian cell lines. Of the 20 gain-of-function variants assessed, 13 were found to alter receptor desensitization properties. Seven variants reduced desensitization at equilibrium, which acts to worsen gain-of-function traits. Six variants accelerated current decay kinetics, which limits gain-of-function traits. All affected patients displayed severe clinical phenotypes with intellectual disability and difficult-to-treat epilepsy. Nevertheless, variants that reduced desensitization at equilibrium were associated with more severe clinical outcomes. This included younger age of first seizure onset (median 0.5 months), movement disorders (dystonia and dyskinesia), epilepsy of infancy with migrating focal seizures (EIMFS) and risk of early mortality. Variants that accelerated current decay kinetics were associated with slightly milder phenotypes with later seizure onset (median 4 months), unclassifiable developmental and epileptic encephalopathies or Lennox-Gastaut syndrome and no movement disorders. Our study reveals that gain-of-function GABRB3 variants can increase or decrease receptor desensitization properties and that there is a correlation with the degree of disease severity. Variants that reduced the desensitization at equilibrium were clustered in the transmembrane regions that constitute the channel pore and correlated with greater disease severity, while variants that accelerated current decay were clustered in the coupling loops responsible for receptor activation and correlated with lesser severity.
Agonist-dependent Single Channel Current and Gating in α4β2δ and α1β2γ2S GABAA Receptors
Publisher: Rockefeller University Press
Date: 28-01-2008
Abstract: The family of γ-aminobutyric acid type A receptors (GABAARs) mediates two types of inhibition in the mammalian brain. Phasic inhibition is mediated by synaptic GABAARs that are mainly comprised of α1, β2, and γ2 subunits, whereas tonic inhibition is mediated by extrasynaptic GABAARs comprised of α4/6, β2, and δ subunits. We investigated the activation properties of recombinant α4β2δ and α1β2γ2S GABAARs in response to GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one (THIP) using electrophysiological recordings from outside-out membrane patches. Rapid agonist application experiments indicated that THIP produced faster opening rates at α4β2δ GABAARs (β ∼1600 s−1) than at α1β2γ2S GABAARs (β ∼ 460 s−1), whereas GABA activated α1β2γ2S GABAARs more rapidly (β ∼1800 s−1) than α4β2δ GABAARs (β & 440 s−1). Single channel recordings of α1β2γ2S and α4β2δ GABAARs showed that both channels open to a main conductance state of ∼25 pS at −70 mV when activated by GABA and low concentrations of THIP, whereas saturating concentrations of THIP elicited ∼36 pS openings at both channels. Saturating concentrations of GABA elicited brief (& ms) openings with low intraburst open probability (PO ∼ 0.3) at α4β2δ GABAARs and at least two “modes” of single channel bursting activity, lasting ∼100 ms at α1β2γ2S GABAARs. The most prevalent bursting mode had a PO of ∼0.7 and was described by a reaction scheme with three open and three shut states, whereas the “high” PO mode (∼0.9) was characterized by two shut and three open states. Single channel activity elicited by THIP in α4β2δ and α1β2γ2S GABAARs occurred as a single population of bursts (PO ∼0.4–0.5) of moderate duration (∼33 ms) that could be described by schemes containing two shut and two open states for both GABAARs. Our data identify kinetic properties that are receptor-subtype specific and others that are agonist specific, including unitary conductance.
Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia
Publisher: Elsevier BV
Date: 07-2016
Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2017
DOI: 10.1038/SREP42810
Abstract: Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (Na V ), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on Na V 1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective Na V toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all Na V subtypes, an increase in the inactivation time constant was observed only at Na V 1.8, while the slope factor of the conductance-voltage curves was significantly increased for Na V 1.7 and peak current was significantly increased for Na V 1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of Na V 1.8 and the tetrodotoxin-sensitive isoforms Na V 1.7 and Na V 1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of Na V isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.
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Cornell University Joan And Sanford I Weill Medical College
Location: United States of America
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Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP120104373
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End Date: 12-2014
Amount: $285,000.00
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View Funded ActivityDiscovery Projects - Grant ID: DP190101390
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