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α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials

Werner Sieghart, Lih-Chu Chiou, Margot Ernst, Jure Fabjan, Miroslav M. Savić and Ming Tatt Lee
Charles France, ASSOCIATE EDITOR
Pharmacological Reviews January 2022, 74 (1) 238-270; DOI: https://doi.org/10.1124/pharmrev.121.000293

Article Figures & Data

Figures

  • Fig. 1
    Fig. 1

    GABAAR subunit composition and arrangement. The majority of GABAARs is composed of two α subunits, two β subunits, and one γ subunit that form a central anion channel with the indicated subunit arrangement when viewed from above. The two α and β subunits can be identical or different. The upper left image depicts the experimentally verified subunit arrangement for the major GABAAR subtype composed of α1βγ2 subunits, and the other three panels depict α6-containing arrangements that have been shown to exist in cerebellar granule cells (Scholze et al., 2020). Each subunit has a principal (+) and a complementary (−) side. The + side contains the large loop C in the extracellular domain that is part of the pharmacological binding sites formed by the interfaces of two subunits. This loop C is schematically depicted as the pointed end of each subunit. The two GABA binding sites are formed by the two β+/α- interfaces. The benzodiazepine binding site (Bz) is formed by the α+/γ2- interface. Receptors containing α1, α2, α3, or α5 subunits form diazepam-sensitive benzodiazepine sites (DS-Bz). Receptors containing α4 or α6 subunits form diazepam-insensitive benzodiazepine binding sites (DI-Bz). Pyrazoloquinolinones (PQs) bind to two distinctive interfaces: to the benzodiazepine binding sites of all αβγ2 receptors with high affinity as silent binders (antagonists, similar to flumazenil) and to the PQ sites of these receptors formed by the α+/β- interfaces as modulators. α6GABAAR-selective pyrazoloquinolinones, such as Compound 6 (PZ-II-029), exert their positive modulatory action via the PQ site at the α6+/β- interface. The δ-containing α6βδ and α1α6βδ receptors presumably have a similar stoichiometry and subunit arrangement as the respective γ2-containing receptors, but this is still a matter of controversy.

  • Fig. 2
    Fig. 2

    GABAAR α6 subunit expression in the mouse brain and trigeminal ganglia. (A) In situ hybridization of a parasagittal mouse whole brain section for Gabra6 mRNA, obtained from Allen Brain Atlas Data Portal by Allen Institute for Brain Science (https://mouse.brain-map.org/experiment/show/308055734). Gabra6 expression is high in cerebellar granule cells but low in olfactory areas, isocortex, hippocampal formation, hypothalamus, midbrain, and pons. (B) Immunohistochemistry demonstrating GABAAR α6 subunit expression in neurons and satellite glial cells of TG in mice. Micrographs are representative mouse TG sections triple immunofluorescence-stained with antibodies against the α6 subunit of GABAA receptors (B-i, B-iii, and B-v, green), NeuN (B-ii and B-iii, blue, neuronal marker), and glutamine synthetase (GS, B-iv and B-v, red, satellite glial cells marker). Modified from Tzeng et al. (2021). Neurons and satellite glial cells are organized in bands or clusters within the ganglion. The spaces between the clusters are filled by nerve fibers, microglia, and macrophages (Legradi et al., 2020).

  • Fig. 3
    Fig. 3

    Representative GABA-evoked currents of recombinant GABAARs. (A) Whole-cell currents elicited by respective submaximal concentrations of GABA recorded from mouse fibroblast L929 cells transfected with α1β3γ2L, α6β3γ2L, and α6β3δ GABAA receptor subunits. Modified from Saxena and Macdonald (1996). (B) Concentration jump experiments in the outside-out patch configuration induced by a saturating GABA concentration (1 mM) recorded from human embryonic kidney 293T cells transfected with α6β3γ2L and α6β3δ GABAA receptor subunits. Modified from Bianchi et al. (2002). Horizontal bars above traces indicate the duration of GABA application.

  • Fig. 4
    Fig. 4

    Chemical structures of GABAAR ligands. BZ, benzodiazepine.

  • Fig. 5
    Fig. 5

    Concentration-response curves of α6GABAAR-selective ligands. Curves are reproduced based on published (Varagic et al., 2013; Chiou et al., 2018; Knutson et al., 2018; Treven et al., 2018), (PCT/US2016/035761) and unpublished data for PZ-II-029/Compound 6 (top), 8-chloro-2-(3-methoxyphenyl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one (LAU159) (middle), and 7-bromo-2-(4-methoxyphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]-quinolin-3-one) (LAU463) (bottom). Data for α6β3γ2 and α6β3δ are presented in blue. At 100% of control current, the response equals that of the GABA-evoked current in the absence of compounds. All measurements were performed with GABA concentrations eliciting 3%–5% and ∼10%–20% of maximum GABA-elicited current for γ2- and δ-containing receptors, respectively. Modulation of α6-containing receptors by the indicated compounds at 100 nM was already stronger than that of receptors containing other α subunits. Deuterated derivatives, such as DK-I-56-1, behave like the respective parent compounds in concentration-response investigations at different receptor subtypes (Knutson et al., 2018).

  • Fig. 6
    Fig. 6

    Simplified schematic representation of cerebellar microcircuitry. Excitatory terminals are indicated by arrowheads and a plus sign, whereas inhibitory terminals are represented by blunt T-ends and a minus sign. The mossy fiber terminal structure that is known as glomerulus is depicted as drop-shaped terminal ending. Granule cells with their schematic processes are emphasized by red color.

  • Fig. 7
    Fig. 7

    5q34 locus of GABAAR genes, GABRA6 gene, and localization of the variants: (A) GABAAR genes in the 5q34 locus are depicted to scale reflecting their respective sizes, with arrows showing the direction of the reading frame. The π subunit encoding gene GABRP is located nearby on the 5q35.1 locus (on the right side of GABRG2). The scale is shown on the right-hand side above the scheme. kbp, kilo base pairs. (B) Enlarged view of GABRA6 with nine exons (E1–E9, boxes), eight introns, and two (5′- and 3′-) flanking regions. The scale is indicated on the right-hand side below the scheme. All variants listed in Table 3 are denoted with black lines. Rs3811995 is part of the 5′-upstream sequence and as such is not transcribed. (C) Mature mRNA and the respective protein precursor are depicted schematically and to a scale wherein one codon equals one amino acid. In the mRNA scheme (upper part of the panel), the relative positions of start and stop codons are marked by yellow lines, exon boundaries by white dashed lines, and the transcribed variants in black lines as in (B). The exon numbers are written in white. In the protein precursor (lower part of the panel), the nonsynonymous variants are indicated by extended black lines. The color code on the protein refers to the localization: gray for the signal peptide (S), purple for all extracellular domains (ECD), dark red for the four transmembrane helices (TM1-4), and green for all intracellular domains (ICD). Note that rs3219151 is part of the 3′-untranslated region on exon 9, and Rs13184586 is a synonymous variant that does not cause a replacement of an amino acid. The 5′- and 3′-untranslated regions of the mRNA are important for many processes pertaining to mRNA structure, fate, and translation. The scale bars above and below the schemes indicate the mRNA and protein sizes, respectively. bp, base pairs; AA, amino acids.

Tables

  • TABLE 1

    Distribution of α6-subunits in the nervous system and in peripheral tissues

    RegionExperimental SubjectsDetection MethodReference
    Central nervous system
    CerebellumHuman post-mortem study
    (schizophrenia and control)    		RT-qPCRBullock et al. (2008)
    Rats (Long Evans)RT-qPCRBullock et al. (2009)
    Rats (undefined)ISHLaurie et al. (1992)
    Rats (Albino)ISHPersohn et al. (1992)
    Rats (Spraque-Dawley)Northern blotMhatre and Ticku (1992)
    Rats (Spraque-Dawley)IHCPirker et al. (2000)
    Gutierrez et al. (1996)
    Mice (C57BL/6J)ISHVarecka et al. (1994)
    Lein et al. (2007)
    α6−/− Mice (C57BL/6)LacZ-Gabra6Jones et al. (1997)
    Mice, chicken, and fishISH
    Autoradiography    		Bahn et al. (1996)
    Cochlear nuclei/
    Cochlear root nuclei    		Rats (Wistar)ISHCampos et al. (2001)
    Rats (Sprague-Dawley)IHCGutierrez et al. (1996)
    Mice (C57BL/6J)ISHVarecka et al. (1994)
    Lein et al. (2007)
    α6−/− Mice (C57BL/6)LacZ-Gabra6Jones et al. (1997)
    Rats (Wistar)RT-PCRGomez-Nieto et al. (2008)
    Cortex (prefrontal)Human post-mortem study
    (AUD and control)    		RT-qPCRGatta et al. (2021)
    Rats (Long Evans)RT-qPCRAgrawal and Dwivedi (2020)
    Cortex (superior frontal)Human post-mortem study
    (autism and control)    		RT-qPCR
    Western blot    		Fatemi et al. (2014)
    HippocampusRats (Sprague-Dawley)RT-qPCR, IHC,
    Western blot    		Yang et al. (2016)
    Inferior colliculus (dorsal)α6−/− Mice (C57BL/6)LacZ-Gabra6Jones et al. (1997)
    Infralimbic areaMice (C57BL/6J)ISHLein et al. (2007)
    Olfactory nerveRats (Sprague-Dawley)IHCGutierrez et al. (1996)
    Olfactory cortex (peduncular area, taenia tecta)Mice (C57BL/6J)ISHLein et al. (2007)
    Orbital layerMice (C57BL/6J)ISHLein et al. (2007)
    Periaqueductal grayAlcol P rats (Wistar)RNA seqMcClintick et al. (2016)
    Parabrachial nucleusMice (C57BL/6J)ISHLein et al. (2007)
    Raphe nucleus (dorsal)Alcol P rats (Wistar)RNA seqMcClintick et al. (2015)
    Retina (inner plexiform layer)Rats (Sprague-Dawley)IHCGutierrez et al. (1996)
    Spinal cordRats (Sprague-Dawley)
    (dorsal horn, layer II)    		IHCGutierrez et al. (1996)
    Turtles
    (motor neurons)    		RT-PCR, IHC,
    Western blot    		Gomez-Nieto et al. (2008)
    Andres et al. (2014)
    Rats (Sprague-Dawley)
    (Vc-C1)    		IHC
    Western blot    		Kramer and Bellinger (2013)
    Kramer and Bellinger (2014)
    Striatum (ventral)Mice (C57BL/6J)
    D3R−/− mice    		RT-PCRLeggio et al. (2015)
    Substantia nigraα6−/− Mice (C57BL/6)LacZ-Gabra6Jones et al. (1997)
    Thalamus (geniculate nuclei)α6−/− Mice (C57BL/6)LacZ-Gabra6Jones et al. (1997)
    Peripheral nervous system
    CochleaMice (CBA/J)RT-PCRDrescher et al. (1993)
    Rats (Wistar)
    (spiral ganglion and organ)    		IHCYamamoto et al. (2002)
    Trigeminal gangliaRats (Sprague-Dawley)IHC and RT-PCRHayasaki et al. (2006)
    Rats (Sprague-Dawley)IHC and qPCRPuri et al. (2011)
    Rats (Sprague-Dawley)IHC
    Western blot    		Puri et al. (2012)
    Kramer and Bellinger (2013)
    Kramer and Bellinger (2014)
    Rats (Wistar)IHCFan et al. (2018)
    Rats (Wistar)RNA seqKogelman et al. (2017)
    Mice (ICR)IHCTzeng et al. (2021)
    Vestibular end-organsRats (Sprague-Dawley)RT-PCRRezaee et al. (1999)
    Peripheral tissues
    T lymphocytesHuman blood samplesRT-qPCRDionisio et al. (2011)
    Jurkat cells (human T lymphocyte cell line)RT-qPCRMendu et al. (2012)
    RT-qPCRAlam et al. (2006)
    Rats (BB strain)
    (CD4+ and CD8+)    		RT-qPCRMendu et al. (2011)
    Rats (Wistar)
    (CD4+ and CD8+)    		RT-qPCR
    Western blot    		Mendu et al. (2012)
    LiverHuman resectionsIHCBautista et al. (2014)
    Lung alveolar (type I and II)Rats (Sprague-Dawley)RT-qPCRJin et al. (2006)
    Pancreatic α-cellsRats (Wistar)RT-qPCRJin et al. (2013)
    Placenta and uterusRats (Wistar)RT-PCRAkinci and Schofield (1999)

    • α6−/− mice, GABAA receptor α6 subunit knockout mice; Alcol P rats, alcohol-preferring rats; autoradiography, [3H]Ro15-4513; AUD, alcohol use disorder; BB strain, congenic Biobreeding strain; CBA/J, a strain of Agouti mice; CD4+: CD4+ T lympocytes; CD8+: CD8+ T lymphocytes; D3R−/− mice, dopamine D3 receptor knockout mice; ICR, Institute of Cancer Research; IHC, immunohistochemistry; ISH, in situ hybridization; LaZ-Gabra6, LacZ expression driven from the Gabra6 locus detected by β-galactosidase staining; Northern blot, Northern blotting for mRNA; PCR, polymerase chain reaction; qPCR, quantitative PCR; RNA seq, RNA sequencing; RT-PCR, reverse-transcription PCR; RT-qPCR, quantitative reverse-transcription PCR; Vc-C1, trigeminal nucleus caudalis and upper cervical region; Western blot, Western blotting for protein.

  • TABLE 2

    Therapeutic potentials of α6GABAAR PAMs based on patient studies and animal models of neuropsychiatric disorders

    DisorderPatient Study/Animal ModelPathophysiological ChangesEffects of α6GABAAR PAMs
    Angelman syndromePost-mortem (human)Cerebellar atrophy, PC, and granule cells loss and lower cerebellar GABA levels (Jay et al., 1991).# THIP (gaboxadol), a δGABAAR agonist, reduced PC abnormal firing and reduced cerebellar ataxia in Ube3a-deficient mice (Egawa et al., 2012).

    * α6GABAR PAMs may achieve similar therapeutic effects in Ube3a-deficient mice and patients with Angelman syndrome.
    Gene association/post-mortem (human)Functional deficit of UBE3A-encoded protein (Kishino et al., 1997; Lalande and Calciano, 2007).
    Ube3a-deficient miceReduced tonic inhibition of cerebellar GCs causes abnormal PC firing and cerebellar ataxia (Egawa et al., 2012).
    Down syndromePostmortem (human)Reduced cerebellar volume and fewer cerebellar GCs (Aylward et al., 1997; Baxter et al., 2000).
    MRI (human)Smaller brain volume with disproportionately smaller cerebellum (Pinter et al., 2001).
    Ts65Dn mouse modelSmaller tonic GABA currents, unchanged α6 subunits, and increased excitability in cerebellar GCs (Szemes et al., 2013).* THIP and α6GABAAR PAMs may restore tonic GABA transmission in cerebellar GCs and alleviate motor deficits in Ts65Dn mice and in patients with Down syndrome.
    Essential tremorPostmortem (human)Cerebellar and PC abnormalities (Louis and Faust, 2020).# THIP suppressed harmaline-induced tremor in wild-type but not in Gabra6−/− or Gabrd−/− mice (Handforth et al., 2018), suggesting an involvement of α6βδ GABAARs.
    fMRI (human)Excessive cerebellar activity (Sharifi et al., 2014).
    Cerebellar PC VGAT deletion miceOnset of induced tremor in wild-type mice coincident with rhythmic PC firing. Tremorgenic agents had no effects in mice with impaired PC output (Brown et al., 2020).
    # α6GABAAR PAMs (Compound 6 and LAU 463 and their deuterated derivatives DK-I-56-1 and DK-I-58-1, respectively) suppressed harmaline-induced action tremor in mice in a manner prevented by intracerebellar furosemide (Huang et al., 2021), suggesting an involvement of cerebellar α6GABAARs.
    Tic disordersMRI (human)Reduced cerebellar gray matter volume (Tobe et al., 2010;
    Sigurdsson et al., 2020).    		# C. inerme leaf juice reduced intractable motor tics in a patient (Fan et al., 2009).
    [11C]flumazenil PET (human)Widespread abnormalities of GABAARs in the brain, increase of GABAARs in bilateral cerebellum (Lerner et al., 2012).# This herb’s extract (Chen et al., 2012) and a bioactive constituent, hispidulin, (Huang et al., 2015), reduced tic-associated responses in mice. Hispidulin acted as an α6GABAAR PAM (Liao et al., 2016).
    PPI test (human)PPI deficit in TS children (Swerdlow et al., 2001).
    # α6GABAAR-selective PAM DK-I-56-1 reduced tic behaviors and PPI deficits in mouse models of tic disorders (Cadeddu et al., 2021).
    ADHDMRI (human)Smaller superior cerebellar vermis (Mackie et al., 2007).* α6GABAAR PAMs may restore tonic GABA inhibition in cerebellar GCs and reduce ADHD phenotypes.
    fMRI (human)Fronto-parieto-cerebellar deficits (Hart et al., 2012).
    PPI test (human)PPI deficit in patients with ADHD (Ornitz et al., 1992).# α6GABAAR PAMs (Compound 6, hispidulin, Ro15-4513, loreclezole) significantly reversed PPI deficits in mice induced with methamphetamine (Chiou et al., 2018).
    Gene associationGIT1 SNP is associated with ADHD phenotypes (Won et al., 2011).
    Git1-knockout miceReduced tonic GABA currents in cerebellar GC and ADHD-like behaviors (Kim et al., 2017).
    # DK-I-56-1 reversed PPI deficits in animal models of tic disorders (Cadeddu et al., 2021).
    Obsessive-compulsive disorderMRI (human)Significant cerebellar enlargement (Pujol et al., 2004; Tobe et al., 2010; Brooks et al., 2016).# α6GABAAR PAMs (Compound 6, hispidulin, Ro15-4513, loreclezole) significantly reversed PPI deficits in mice induced with methamphetamine (Chiou et al., 2018).
    fMRI (human)Decreased functional connectivity between the cerebral cortex and cerebellum in executive control and emotion-processing networks (Anticevic et al., 2014; Xu et al., 2019).
    # DK-I-56-1 reversed PPI deficits in animal models of tic disorders (Cadeddu et al., 2021).
    PPI test (human)PPI deficit (Swerdlow et al., 1993; Ahmari et al., 2012).
    Huntington diseasePost-mortem
    (Human)    		Cerebellar atrophy and loss of PCs correlate with motor deficits (Rub et al., 2013; Singh-Bains et al., 2019).# α6GABAAR-selective PAMs might eliminate PPI deficits (Chiou et al., 2018; Cadeddu et al., 2021) and possibly also reduce motor symptoms of Huntington disease.
    MRI (human)Aberrant cerebellar diffusion and reduced cerebellar volume associated with impaired motor function and increased psychiatric symptoms (Rees et al., 2014).
    PPI test (human)PPI deficit in patients with Huntington disease (Swerdlow et al., 1995).
    SchizophreniaPost-mortem (human)Loss of cerebellar PCs (Maloku et al., 2010).# α6GABAAR-selective PAMs (Compound 6, hispidulin, Ro15-4513, loreclezole) rescued PPI deficits (Chiou et al., 2018).
    Increased α6 subunit expression in the superior frontal cortex (Fatemi et al., 2017).
    Decreased GAD67, GAD65, and GAT-1 and increased GABRA6 mRNA in the cerebellum. (Fatemi et al., 2005; Bullock et al., 2008). However, no change in GABRA6 mRNA and protein expression in the cerebellum (Fatemi et al., 2013).# Compound 6, DK-I-56-1, and hispidulin rescued social withdrawal and cognitive deficits (Chiou et al., 2019; Mouri et al., 2020) in mouse models mimicking schizophrenia.
    MRI (human)Volume reductions in posterior superior vermis as well as in frontal and temporal lobe, thalamus, and left cerebellar hemisphere, supporting the model of cognitive dysmetria in schizophrenia (Volz et al., 2000; Okugawa et al., 2002).
    Reduced cerebellar volume associated with negative and psychotic symptom duration and psychosocial impairment (Wassink et al., 1999).
    fMRI (human)Impaired PFC-cerebellum functional connectivity associated with negative symptoms (Brady et al., 2019).
    PPI test (human)PPI deficit (Braff et al., 1978; San-Martin et al., 2020).
    PET (human)Dysfunctional prefrontal thalamic-cerebellar circuitry (Andreasen et al., 1996).
    Gene association
    (Human)    		GABRA6 rs3219151 C>T associated with schizophrenia susceptibility (Gong et al., 2013).
    5q34 mutations are associated with schizophrenia and cause lower GABRA6 expression (Petryshen et al., 2005).
    PCP-chronically treated ratsDecreased GAD65 and GAD67 and increased Gabra6 mRNA at cerebellar Golgi-granule synapses (Bullock et al., 2009).
    Stress-associated disordersMRI (adolescents with early-life stress)Reduced cerebellar gray matter volume (Walsh et al., 2014; Lim et al., 2018).* α6GABA AR PAMs may attenuate functional deficits in the cerebellum and reduce symptoms of stress-associated disorders.
    fMRI (adults with early-life stress)Reduced blood flow and neuronal activity in vermis (Anderson et al., 2002).
    MRI (pediatric PTSD)Reduced cerebellar volume (De Bellis et al., 2015).
    MRI (adult PTSD)Reduced cerebellar volume (Baldacara et al., 2012).
    PPI test (human)PPI deficits in patients with premenstrual dysphoric disorder (Kask et al., 2008).
    PPI deficits in women with PTSD (Pineles et al., 2016) and in trauma-affected refugees with PTSD (Meteran et al., 2019).
    Gene associationGABRA6 rs3219151 T carriers had greater responses to stress (Uhart et al., 2004; Lynch et al., 2015).
    GABRA6 rs3219151 T male carriers had higher cortisol levels and higher abdominal obesity (Rosmond et al., 2002).
    GABRA6 rs3811995 C carriers had higher incidents of externalizing behaviors and substance use (Trucco et al., 2016).
    Cerebellar GCs Gabrd-KO miceIncreased stress-related behaviors (Rudolph et al., 2020).
    Anxiety disordersPPI test (human)PPI deficit in patients with panic disorder (Ludewig et al., 2002).# α6GABAAR PAMs (Compound 6, hispidulin, Ro15-4513, loreclezole) significantly reversed PPI deficits in mice induced with methamphetamine (Chiou et al., 2018).
    Gene association (human)GABRA6 rs3219151 T carriers had higher anxiety, depression, and suicide risk after recent negative life events (Gonda et al., 2017).
    GABRA6 rs3219151 C carriers associated with panic disorder, but T carriers had stronger reactions to a dynamic fearful face (Inoue et al., 2015).# DK-I-56-1 reversed PPI deficits in animal models of tic disorders (Cadeddu et al., 2021).
    Panic disorder–associated miRNA reduced GABRA6 expression in a Luciferase-reporter assay (Muinos-Gimeno et al., 2011).* α6GABAAR PAMs may attenuate functional deficits in cerebellum and reduce symptoms of anxiety and panic disorders.
    Cerebellar GCs Gabrd-KO miceIncreased anxiety-related behaviors (Rudolph et al., 2020).
    Depression/bipolar disorderPost-mortem (human)Decreased cerebellar GAD65 and GAD67 (depression/bipolar disorder) (Fatemi et al., 2005).* α6GABAAR PAMs might compensate low GABA levels in cerebellum and ameliorate some symptoms of these disorders.
    Loss of cerebellar PCs in bipolar disorder (Maloku et al., 2010).
    * Increased α6 subunits in depression/bipolar patients might be an incomplete compensatory change due to impaired GABAergic transmission. α6GABAAR PAMs might compensate α6GABAAR deficits and ameliorate depressive symptoms.
    Increased α6 subunits in the lateral cerebellum (major depression) (Fatemi et al., 2013).
    Increased α6 subunits in the superior frontal cortex (bipolar disorder) (Fatemi et al., 2017).
    MRI (human)Reduced cerebellar volume (bipolar disorder) (Baldacara et al., 2012).
    Gene association (human)GABRA6 rs3219151 C-allele
    associated with major depression (Inoue et al., 2015).
    GABRA6 rs3811993 missense variant associated with bipolar disorder (Ament et al., 2015).
    Adolescent rats with maternal separationDecreased Gabra6 mRNA and α6 subunits in the hippocampus and depressive-like behavior (Yang et al., 2016).
    Hippocampal Gabra6-KD ratsInducing depressive-like behaviors (Yang et al., 2016).
    Autism spectrum disorderPostmortem (human)Reduced cerebellar PC size and number (Fatemi et al., 2002a; Whitney et al., 2008).* α6GABA AR PAMs may compensate for reduced GABA and α6GABAAR levels and attenuate symptoms in autism spectrum disorders.
    Decreased GAD65 and GAD67 in parietal and cerebellar cortices (Fatemi et al., 2002b; Yip et al., 2007).
    Fewer α6, β2, δ, and γ2 subunits in the superior frontal cortex (Fatemi et al., 2014).
    MRI (human)Reduced cerebellar gray matter in vermis associated with social and interaction deficits (Riva et al., 2013; D'Mello et al., 2015)
    # α6GABAAR PAMs (Compound 6, hispidulin, Ro15-4513, loreclezole) significantly reversed PPI deficits in mice induced with methamphetamine (Chiou et al., 2018). # DK-I-56-1 reduced tic-like jerks in animal models of tic disorders (Cadeddu et al., 2021).
    PPI (human)PPI deficit in children/adolescents but not adults (Cheng et al., 2018).
    Alcohol use disorderPostmortem (chronic excessive alcoholics)Cerebellar atrophy (Torvik and Torp, 1986).* Cerebellar changes in humans and rats suggest that α6GABAAR PAMs may have some effects also in this disorder. Because of the multiple changes in other receptors and proteins, these effects are difficult to predict.
    Reduced PC volume but increased granular layer in the cerebellum (Andersen, 2004).
    Decreased cerebellar δ, but unchanged α6 protein and decreased PFC α6 and δ mRNA (Gatta et al., 2017; Gatta et al., 2021).
    Gene association (human)α6Ser385 carriers in offspring of alcoholics had the lowest alcohol sensitivity during adolescence (Iwata et al., 1999) and were more vulnerable to become alcoholics later on (Schuckit et al., 1999; Hu et al., 2005).
    GABRA6 rs3219151 T allele carriers were significantly associated with alcohol dependence (Loh et al., 1999; Sander et al., 1999; Radel et al., 2005; Sahni et al., 2019).
    Alcohol-dependent patients carrying the GABRA6 rs3219151 TT or CC alleles differentially respond to naltrexone or acamprosate treatment, respectively (Ooteman et al., 2009).* Alcohol-dependent patients carrying the GABRA6 rs3219151 CC alleles might benefit from treatment with α6GABAAR PAMs.
    Repeated ethanol-treated ratsIncreased cerebellar α6 but decreased α1 protein (Mhatre and Ticku, 1992; Morrow et al., 1992).
    Alcohol-preferring ratsIncreased α6 and δ but decreased γ2 mRNAs in the periaqueductal gray and dorsal raphe nucleus (McClintick et al., 2015, 2016).
    Trigeminal-related painTMJ inflammation (rats)CFA induced stronger TMJ pain responses in rats with reduced TG Gabra6 expression (Puri et al., 2012).* α6GABAARs PAMs may reduce TMJ or trigeminal-related orofacial pain.
    Trigeminal neuropathic pain (rats)Infraorbital nerve ligation induced trigeminal neuropathy (Vasovic et al., 2019).
    # α6GABAAR-selective PAM DK-I-56-1 suppressed infraorbital nerve ligation-induced nociceptive responses (Vasovic et al., 2019).
    MigraineTGVS-activated ratsCapsaicin (i.c.) induces central and peripheral sensitization in the TGVS (Fan et al., 2018).# α6GABAAR-selective PAMs (Compound 6, Ro15-4513, loreclezole) reduced migraine-related peripheral and central sensitization of TGVS. These effects were mimicked by topiramate and inhibited by systemic furosemide (Fan et al., 2018).
    Nitroglycerin-repeatedly treated miceDecreased GAD65, unchanged GAT1, and unchanged α6GABAARs in trigeminal ganglia (Tzeng et al., 2021).
    # α6GABAAR-selective PAM (DK-I-56-1) abolished and prevented migraine-like grimaces in a manner mimicked by sumatriptan and topiramate, respectively, and blocked by systemic furosemide (Tzeng et al., 2021).

    • α6GABAAR, α6 subunit-containing GABAA receptor; ADHD, attention deficit hyperactivity disorder; CFA, complete Freund´s adjuvant; GAD65, glutamate decarboxylase 65 kDa; GAD67, glutamate decarboxylase 67 kDa; GAT-1, GABA transporter 1; GC, granule cell; GIT1/Git1, G-protein-coupled–receptor kinase-interacting protein-1; KO, knockout; i.c., intracisternally; ICR, Institute of Cancer Research; KO, knockout; MRI, magnetic resonance imaging; fMRI, functional magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NTG, nitroglycerin; PAM, positive allosteric modulator; PC, Purkinje cells; PET, positron emission tomography; PFC, prefrontal cortex; PTSD, post-traumatic stress disorder; PPI, prepulse inhibition; SNP, single nucleotide polymorphism; TG, trigeminal ganglia; TGVS, trigemino-vascular system; THIP, 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (gaboxadol); TMJ, temporomandibular joint; TS, Tourette syndrome; VGAT, vesicular GABA transporter; wt, wild type; *, hypothesis to be proven; #, hypothesis proven.

  • TABLE 3

    GABRA6 variants reported in genetic studies

    Nucleotide mutation data are taken from dbSNP database (Sherry et al., 2001). Where the mutation resulted in an alteration of the protein sequence, the change is listed under AA consequence. The numbering of amino acids includes the signal peptide [as suggested in The Universal Protein Resource Knowledgebase (UniProtKB)] (Consortium, 2019). The listed publications are separated according to the alternative names used.

    Rs NumberMutationConsequence TypeAA ConsequenceReferencesOriginal and Alternative Namesa
    rs373363000C>TCSVArg46TrpDibbens et al. (2009)
    Hernandez et al. (2011)    		α6R46W
    rs3219151T>Cb3′UTR variant/Loh et al. (1999)
    Sander et al. (1999)
    Rosmond et al. (2002)
    Radel et al. (2005)
    Ooteman et al. (2009)
    Prasad et al. (2014)c    		1519T>C
    Park et al. (2006)1519
    Han et al. (2008)T+1519C
    Kumari et al. (2011)1512T>C
    Uhart et al. (2004)
    Arias et al. (2012)
    Lynch et al. (2015)    		T1521C
    Yamada et al. (2003)c.1497C>T
    Gong et al. (2013)rs3219151(C>T GABRA6)
    Inoue et al. (2015)
    Gonda et al. (2017)
    Sahni et al. (2019)    		rs3219151
    rs3811995C>T5′UTR variant/Trucco et al. (2016)rs3811995
    rs34907804C>TCSVPro404SerdIwata et al. (1999)
    Schuckit et al. (1999)
    Hoffman et al. (2002)
    Sen et al. (2004)
    Hu et al. (2005)
    Radel et al. (2005)
    Lucht et al. (2006)    		Pro385Serd
    rs3811993C>TCSVThr187MetAment et al. (2015)rs3811993
    rs13184586C>A,GCSVAla335AlaRadel et al. (2005)1031G>C

    • AA, amino acid; CSV, coding sequence variant.

    • ↵aNucleotide or amino-acid numbers vary between the listed references. In some cases, the numbering of the mutated nucleotide/amino acid is mapped to a known cDNA/amino-acid sequence. This sequence can vary from the entire genomic sequence because of various reasons (i.e., differential splicing, alternative transcription start sites), producing a discrepancy in numbering of the same mutation between different publications (Antonarakis, 1998).

    • ↵bThe T- and C-variants are comparably abundant. Depending on the population investigated in the individual studies, the more abundant variant is considered wild-type and the less abundant is considered mutated, resulting in either T>C or C>T.

    • ↵cThe publication uses both 1519T>C and rs3219151 as identifiers

    • ↵dThe difference in amino-acid numbering accounts for the signal peptide inclusion or exclusion.

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α6-Containing GABAA Receptors: Therapeutic Potentials

Werner Sieghart, Lih-Chu Chiou, Margot Ernst, Jure Fabjan, Miroslav M. Savić and Ming Tatt Lee
Pharmacological Reviews January 1, 2022, 74 (1) 238-270; DOI: https://doi.org/10.1124/pharmrev.121.000293
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