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.

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.

Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly

2002 ◽  
Vol 103 (5) ◽  
pp. 481-487 ◽  
Author(s):  
Dina Zekry ◽  
Charles Duyckaerts ◽  
Robert Moulias ◽  
Joël Belmin ◽  
Caroline Geoffre ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
The Elderly ◽  
Vascular Lesions ◽  
The Brain

HIV infection across aging: Synergistic effects on intrinsic functional connectivity of the brain

2019 ◽  
Vol 88 ◽  
pp. 19-30 ◽  
Author(s):  
Anna R. Egbert ◽  
Bharat Biswal ◽  
Keerthana Deepti Karunakaran ◽  
Agnieszka Pluta ◽  
Tomasz Wolak ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Hiv Infection ◽  
Synergistic Effects ◽  
Intrinsic Functional Connectivity ◽  
The Brain

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 Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0131486 ◽  
Author(s):  
Charlotte D’Hulst ◽  
Inge Heulens ◽  
Nathalie Van der Aa ◽  
Karolien Goffin ◽  
Michel Koole ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Gabaa Receptors ◽  
Fragile X ◽  
Emission Tomography ◽  
Pet Quantification ◽  
Positron Emission ◽  
The Brain

Cluster analysis in kinetic modelling of the brain: a noninvasive alternative to arterial sampling

NeuroImage ◽  
2004 ◽  
Vol 21 (2) ◽  
pp. 483-493 ◽  
Author(s):  
Matthew Liptrot ◽  
Karen H Adams ◽  
Lars Martiny ◽  
Lars H Pinborg ◽  
Markus N Lonsdale ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Kinetic Modelling ◽  
Arterial Sampling ◽  
The Brain

scholarly journals Synergistic effects of treating the spinal cord and brain in CLN1 disease

2017 ◽  
Vol 114 (29) ◽  
pp. E5920-E5929 ◽  
Author(s):  
Charles Shyng ◽  
Hemanth R. Nelvagal ◽  
Joshua T. Dearborn ◽  
Jaana Tyynelä ◽  
Robert E. Schmidt ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Life Span ◽  
Motor Function ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Synergistic Effects ◽  
Intrathecal Administration ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Brain And Spinal Cord ◽  
The Brain

Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1−/−) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1−/− mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1−/− mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.

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