Last update 19 Sep 2024

GABRB2

Last update 19 Sep 2024

Basic Info

Synonyms

GABA(A) receptor subunit beta-2, GABA(A) receptor, beta 2, GABRB2

+ [3]

Introduction

Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:8264558, PubMed:19763268, PubMed:27789573, PubMed:29950725). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:23909897, PubMed:25489750). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (By similarity). The alpha1/beta2/gamma2 receptor and the alpha2/beta2/gamma2 receptor exhibit synaptogenic activity (PubMed:23909897, PubMed:25489750). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity).

Drugs associated with GABRB2

U-89267

Target

GABRA1 x GABRB2 x GABRG2

Mechanism

GABRA1 inhibitors [+2]

Active Org.-

Originator Org.

Pharmacia & Upjohn Co., Inc.

Active Indication-

Inactive Indication

Anxiety Disorders

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

2-261

Target

GABRB2 x GABRB3

Mechanism

GABRB2 modulators [+1]

Active Org.-

Originator Org.

University of California, Irvine Extension

Active Indication-

Inactive Indication

Neuralgia

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GABRB2

100 Translational Medicine associated with GABRB2

0 Patents (Medical) associated with GABRB2

152

Literatures (Medical) associated with GABRB2

01 Oct 2024·Neuropharmacology

The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms

Article

Author: Homanics, Gregg E ; Shawlot, William ; Blednov, Yuri A ; Messing, Robert O ; Smalley, Joshua L ; Moss, Stephen J ; Mayfield, Jody ; Osterndorff-Kahanek, Elizabeth A ; Mason, Sonia

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABA_A β3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABA_A β1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in β1 subunit expression or phosphorylation at other residues. β1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of β1-containing GABA_A receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.

01 Aug 2024·Neuroscience

The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABAAR function

Article

Author: Xu, Di ; He, Zhiyong ; Zhao, Yan-Wen ; Zhang, Xiong ; Xu, Shi-Shi ; Huang, Ruoke ; Li, Peijun ; Li, Ping-Ping ; Zhou, Yue-Yuan ; Gao, Li ; Lv, Jia-Nan ; Fu, Xiaoqin

Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABA_AR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABA_AR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABA_AR channel function, we conducted transient expression experiments using GABA_AR subunits in HEK293T cells. The GABA_ARs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABA_AR containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABA_AR. We propose that GABRB2 variant F224S is pathogenic and GABA_ARs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.

01 Aug 2024·eBioMedicine

Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

Article

Author: Ortiz de la Rosa, Sebastián ; Bonanni, Paolo ; Klepper, Joerg ; Auvin, Stéphane ; Specchio, Nicola ; Chebib, Mary ; Baer, Sarah ; Lemke, Johannes R ; Ahring, Philip Kiær ; Minghetti, Sara ; Trivisano, Marina ; Weckhuysen, Sarah ; Michaeli-Yossef, Yael ; Meridda, Catherine ; Rubboli, Guido ; Rossi, Alessandra ; Amor, David ; Jensen, Anders A ; Meyer, Pierre ; Salpietro, Vincenzo ; Milh, Mathieu ; Maroofian, Reza ; Absalom, Nathan L ; Johannesen, Katrine Marie ; Møller, Rikke Steensbjerre ; Chua, Han Chow ; Bruel, Ange-Line ; Vincent-Devulder, Aline ; Christophersen, Palle ; Yu Liao, Vivian Wan ; Mohammadi, Nazanin Azarinejad ; Patel, Chirag

BACKGROUNDVariants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABA_A) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants.METHODSGenetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function.FINDINGSElectrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants.INTERPRETATIONThe data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes.FUNDINGThis work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

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GABRB2

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