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Altered Channel Conductance States and Gating of GABA Receptors by a Pore Mutation Linked to Dravet Syndrome.
Hernandez CC, Kong W, Hu N, Zhang Y, Shen W, Jackson L, Liu X, Jiang Y, Macdonald RL
(2017) eNeuro 4:
MeSH Terms: Animals, Cell Membrane, Cerebral Cortex, Epilepsies, Myoclonic, HEK293 Cells, Humans, Inhibitory Postsynaptic Potentials, Mice, Inbred C57BL, Miniature Postsynaptic Potentials, Models, Molecular, Mutation, Missense, Neurons, Receptors, GABA-A, Recombinant Proteins, Zinc
Show Abstract · Added April 6, 2017
We identified a missense mutation, P302L, in the γ-aminobutyric acid type A (GABA) receptor γ2 subunit gene in a patient with Dravet syndrome using targeted next-generation sequencing. The mutation was in the cytoplasmic portion of the transmembrane segment M2 of the γ2 subunit that faces the pore lumen. GABA receptor α1 and β3 subunits were coexpressed with wild-type (wt) γ2L or mutant γ2L(P302L) subunits in HEK 293T cells and cultured mouse cortical neurons. We measured currents using whole-cell and single-channel patch clamp techniques, surface and total expression levels using surface biotinylation and Western blotting, and potential structural perturbations in mutant GABA receptors using structural modeling. The γ2(P302L) subunit mutation produced an ∼90% reduction of whole-cell current by increasing macroscopic desensitization and reducing GABA potency, which resulted in a profound reduction of GABA receptor-mediated miniature IPSCs (mIPSCs). The conductance of the receptor channel was reduced to 24% of control conductance by shifting the relative contribution of the conductance states from high- to low-conductance levels with only slight changes in receptor surface expression. Structural modeling of the GABA receptor in the closed, open, and desensitized states showed that the mutation was positioned to slow activation, enhance desensitization, and shift channels to a low-conductance state by reshaping the hour-glass-like pore cavity during transitions between closed, open, and desensitized states. Our study revealed a novel γ2 subunit missense mutation (P302L) that has a novel pathogenic mechanism to cause defects in the conductance and gating of GABA receptors, which results in hyperexcitability and contributes to the pathogenesis of the genetic epilepsy Dravet syndrome.
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15 MeSH Terms
Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an α1 adrenergic receptor-dependent manner.
Williams MA, Li C, Kash TL, Matthews RT, Winder DG
(2014) Neuropharmacology 86: 116-24
MeSH Terms: Animals, Dopaminergic Neurons, Electric Capacitance, Electric Impedance, Excitatory Postsynaptic Potentials, Glutamic Acid, Green Fluorescent Proteins, Male, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Transgenic, Miniature Postsynaptic Potentials, Norepinephrine, Promoter Regions, Genetic, Raphe Nuclei, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, alpha-2, Tyrosine 3-Monooxygenase, Ventral Tegmental Area
Show Abstract · Added August 21, 2014
Dopaminergic innervation of the extended amygdala regulates anxiety-like behavior and stress responsivity. A portion of this dopamine input arises from dopamine neurons located in the ventral lateral periaqueductal gray (vlPAG) and rostral (RLi) and caudal linear nuclei of the raphe (CLi). These neurons receive substantial norepinephrine input, which may prime them for involvement in stress responses. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase promoter, we explored the physiology and responsiveness to norepinephrine of these neurons. We find that RLi dopamine neurons differ from VTA dopamine neurons with respect to membrane resistance, capacitance and the hyperpolarization-activated current, Ih. Further, we found that norepinephrine increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) on RLi dopamine neurons. This effect was mediated through the α1 adrenergic receptor (AR), as the actions of norepinephrine were mimicked by the α1-AR agonist methoxamine and blocked by the α1-AR antagonist prazosin. This action of norepinephrine on sEPSCs was transient, as it did not persist in the presence of prazosin. Methoxamine also increased the frequency of miniature EPSCs, indicating that the α1-AR action on glutamatergic transmission likely has a presynaptic mechanism. There was also a modest decrease in sEPSC frequency with the application of the α2-AR agonist UK-14,304. These studies illustrate a potential mechanism through which norepinephrine could recruit the activity of this population of dopaminergic neurons.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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2 Members
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20 MeSH Terms
Ampakine CX516 ameliorates functional deficits in AMPA receptors in a hippocampal slice model of protein accumulation.
Kanju PM, Parameshwaran K, Sims C, Bahr BA, Shonesy BC, Suppiramaniam V
(2008) Exp Neurol 214: 55-61
MeSH Terms: Animals, Dioxoles, Excitatory Postsynaptic Potentials, Hippocampus, Lysosomes, Miniature Postsynaptic Potentials, Neurons, Organ Culture Techniques, Patch-Clamp Techniques, Piperidines, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Signal Processing, Computer-Assisted, Synaptic Transmission
Show Abstract · Added July 2, 2013
AMPAkines are positive modulators of AMPA receptors, and previous work has shown that these compounds can facilitate synaptic plasticity and improve learning and memory in both animals and humans; thus, their role in the treatment of cognitive impairment is worthy of investigation. In this study, we have utilized an organotypic slice model in which chloroquine-induced lysosomal dysfunction produces many of the pathogenic attributes of Alzheimer's disease. Our previous work demonstrated that synaptic AMPA receptor function is impaired in hippocampal slice cultures exhibiting lysosomal dysfunction leading to protein accumulation. The present study investigated the effect of the AMPAkine CX516 on AMPAR-mediated synaptic transmission as well as the CX516 induced modification of single channel AMPA receptor properties in this organotypic slice-culture model. In whole cell recordings from CA1 pyramidal neurons in chloroquine-treated slices we observed a significant decrease in AMPAR-mediated mEPSC frequency and amplitude indicating synaptic dysfunction. Following application of CX516, these parameters returned to nearly normal levels. Similarly, we report chloroquine-induced impairment of AMPAR single channel properties (decreased probability of opening and mean open time), and significant recovery of these properties following CX516 administration. These results suggest that AMPA receptors may be potential pharmaceutical targets for the treatment of neurodegenerative diseases, and highlights AMPAkines, in particular, as possible therapeutic agents.
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1 Members
0 Resources
15 MeSH Terms