3-fluoro-GABA enantiomers: exploring the conformation of GABA binding to GABAA receptors and GABA aminotransferase

2011 ◽  
Vol 3 (2) ◽  
pp. 189-195 ◽  
Author(s):  
David O’Hagan
Keyword(s):  
Gabaa Receptors ◽  
Gaba Aminotransferase ◽  
Gaba Binding

scholarly journals Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies

Brain ◽  
2019 ◽  
Vol 142 (7) ◽  
pp. 1938-1954 ◽  
Author(s):  
Ciria C Hernandez ◽  
Wenshu XiangWei ◽  
Ningning Hu ◽  
Dingding Shen ◽  
Wangzhen Shen ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Gabaa Receptors ◽  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Inhibitory Synapses ◽  
Causative Gene ◽  
Gabaergic Neurotransmission ◽  
Gaba Binding ◽  
Patients With Epilepsy

Abstract We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.

scholarly journals The desensitization pathway of GABAA receptors, one subunit at a time

2020 ◽  
Author(s):  
Marc Gielen ◽  
Nathalie Barilone ◽  
Pierre-Jean Corringer
Keyword(s):  
Gabaa Receptors ◽  
Synergistic Effects ◽  
Kinetic Modelling ◽  
Concerted Mechanism ◽  
Inhibitory Synaptic Transmission ◽  
Asymmetric Pattern ◽  
Gaba Binding ◽  
Conformational Landscape ◽  
Fast Activation ◽  
The Brain

AbstractGABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, whose conformational pathway remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.

scholarly journals Benzodiazepines Modulate GABAA Receptors by Regulating the Preactivation Step after GABA Binding

2012 ◽  
Vol 32 (17) ◽  
pp. 5707-5715 ◽  
Author(s):  
M. C. Gielen ◽  
M. J. Lumb ◽  
T. G. Smart
Keyword(s):  
Gabaa Receptors ◽  
Gaba Binding

scholarly journals The desensitization pathway of GABAA receptors, one subunit at a time

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marc Gielen ◽  
Nathalie Barilone ◽  
Pierre-Jean Corringer
Keyword(s):  
Gabaa Receptors ◽  
Synergistic Effects ◽  
Kinetic Modelling ◽  
Concerted Mechanism ◽  
Inhibitory Synaptic Transmission ◽  
Asymmetric Pattern ◽  
Gaba Binding ◽  
Conformational Landscape ◽  
Fast Activation ◽  
The Brain

Abstract GABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, the conformational pathway of which remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.

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