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GABAA receptor α5 subunit

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Target not currently curated in GtoImmuPdb

Target id: 408

Nomenclature: GABAA receptor α5 subunit

Family: GABAA receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 462 15q12 GABRA5 gamma-aminobutyric acid type A receptor subunit alpha5 45
Mouse 4 463 7 33.52 cM Gabra5 gamma-aminobutyric acid type A receptor subunit alpha 5
Rat 4 464 1q22 Gabra5 gamma-aminobutyric acid type A receptor subunit alpha 5 27
Previous and Unofficial Names Click here for help
gamma-aminobutyric acid receptor subunit alpha-5 | gamma-aminobutyric acid (GABA) A receptor, alpha 5 | gamma-aminobutyric acid (GABA) A receptor, subunit alpha 5 | gamma-aminobutyric acid (GABA) A receptor | gamma-aminobutyric acid type A receptor alpha5 subunit | gamma-aminobutyric acid type A receptor alpha 5 subunit
Database Links Click here for help
Alphafold P31644 (Hs), Q8BHJ7 (Mm), P19969 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL5112 (Hs), CHEMBL2304 (Mm), CHEMBL300 (Rn)
DrugBank Target P31644 (Hs), P31644 (Hs)
Ensembl Gene ENSG00000186297 (Hs), ENSMUSG00000055078 (Mm), ENSRNOG00000010803 (Rn)
Entrez Gene 2558 (Hs), 110886 (Mm), 29707 (Rn)
Human Protein Atlas ENSG00000186297 (Hs)
KEGG Gene hsa:2558 (Hs), mmu:110886 (Mm), rno:29707 (Rn)
OMIM 137142 (Hs)
Pharos P31644 (Hs)
RefSeq Nucleotide NM_000810 (Hs), NM_176942 (Mm), NM_017295 (Rn)
RefSeq Protein NP_000801 (Hs), NP_795916 (Mm), NP_058991 (Rn)
UniProtKB P31644 (Hs), Q8BHJ7 (Mm), P19969 (Rn)
Wikipedia GABRA5 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
GABAA receptor β3 subunit
GABAA receptor β2 subunit
GABAA receptor γ2 subunit
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
Heteromeric GABAA receptors can be formed from the proteins listed in the table above. These receptors generally consist of 2 α, 2 β and 1 γ subunit. Examples of GABAA receptors containing the α5 subunit include α5β3γ2 and α5β2γ2.
Natural/Endogenous Ligands Click here for help
GABA
5α-pregnan-3α-ol-20-one
tetrahydrodeoxycorticosterone
Zn2+

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CGS8216 Small molecule or natural product Click here for species-specific activity table Hs Inverse agonist 9.6 pKi 25
⤷ pKi 9.6 (Ki 2.5x10-10 M) [25]
ZK93423 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 8.4 pKi 9
⤷ pKi 8.4 (Ki 4.5x10-9 M) [9]
[3H]muscimol Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist - -
⤷ [Binds to: GABA site]
isoguvacine Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: GABA site]
isonipecotic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - -
⤷ [Binds to: GABA site]
muscimol Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: GABA site]
piperidine-4-sulphonic acid Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: GABA site]
gaboxadol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - -
⤷ [Binds to: GABA site]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bicuculline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist - -
⤷ [Binds to: GABA site]
[3H]gabazine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: GABA site]
gabazine Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: GABA site]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
picrotoxin Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
TBPS Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
[35S]TBPS Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - no - - - no
⤷ [Binds to: anion channel]
Not voltage dependent
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
triazolam Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Positive 8.4 pKd - no 23
⤷ pKd 8.4 (Kd 4x10-9 M) [23]
Not voltage dependent
Description: Binding affinity to GABAA receptor α5β2γ2.
compound 20 [PMID: 35584373] Small molecule or natural product Hs Negative 8.4 pKd - no 41
⤷ pKd 8.4 (Kd 4.1x10-9 M) [41]
Not voltage dependent
flumazenil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs - 9.2 pKi - no 38
⤷ pKi 9.2 (Ki 6x10-10 M) [Binds to: benzodiazepine site] Antagonist at α1 receptors, but allosteric modulator at other subtypes. [38]
Not voltage dependent
Description: Affinity measured using α5β3γ2 receptors.
triazolam Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Positive 8.8 pKi - no 25
⤷ pKi 8.8 (Ki 1.54x10-9 M) [25]
Not voltage dependent
Description: Binding affinity for human recombinant GABAA receptor α5β3γ2.
basmisanil Small molecule or natural product Ligand has a PDB structure Hs Negative 8.3 pKi - no 3
⤷ pKi 8.3 (Ki 4.7x10-9 M) [3]
Not voltage dependent
Description: Binding affinity determined in a radioligand displacement assay: test compound competition for [3H]flumazenil at α5β3γ2 GABAA channels transiently expressed in HEK293 cells.
flunitrazepam Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Positive 8.3 pKi - no 22
⤷ pKi 8.3 (Ki 5.5x10-9 M) [Binds to: benzodiazepine site] [22]
Not voltage dependent
Description: Assay using recombinant GABAA channels with subunit composition; α5β1γ2.
ONO-8590580 Small molecule or natural product Hs Negative 8.1 pKi - no 26
⤷ pKi 8.1 (Ki 7.9x10-9 M) [Binds to: benzodiazepine site] [26]
Not voltage dependent
alprazolam Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Positive 8.0 pEC50 - no 1
⤷ pEC50 8.0 (EC50 1x10-8 M) [Binds to: benzodiazepine site] [1]
Not voltage dependent
Zn2+ Click here for species-specific activity table Ligand is endogenous in the given species Hs Inhibition - - - no
⤷
Not voltage dependent
α3IA Small molecule or natural product Click here for species-specific activity table Hs Inverse agonist - - - no 38
⤷ [Binds to: benzodiazepine site] [38]
Not voltage dependent
α5IA Small molecule or natural product Click here for species-specific activity table Hs Inverse agonist - - - no 38
⤷ [Binds to: benzodiazepine site] partially selective [38]
Not voltage dependent
5α-pregnan-3α-ol-20-one Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
bretazenil Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
DMCM Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inverse agonist - - - no 37
⤷ [Binds to: benzodiazepine site] [37]
Not voltage dependent
L655708 Small molecule or natural product Hs Inverse agonist - - - no 37
⤷ [Binds to: benzodiazepine site] high affinity, partially selective [37]
Not voltage dependent
L838417 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist - - - no 38
⤷ [Binds to: benzodiazepine site] partially selective [38]
Not voltage dependent
MRK016 Small molecule or natural product Click here for species-specific activity table Hs Inverse agonist - - - no 38
⤷ [Binds to: benzodiazepine site] partially selective [38]
Not voltage dependent
ocinaplon Small molecule or natural product Click here for species-specific activity table Hs Partial agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
Ro15-4513 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
Ro19-4603 Small molecule or natural product Click here for species-specific activity table Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
RO4938581 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inverse agonist - - - no 38
⤷ [Binds to: benzodiazepine site] higher affinity, partially selective [38]
Not voltage dependent
RY024 Small molecule or natural product Hs Inverse agonist - - - no 38
⤷ [Binds to: benzodiazepine site] high affinity, partially selective [38]
Not voltage dependent
tetrahydrodeoxycorticosterone Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
TP003 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
TPA023 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
ZK93426 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[3H]flunitrazepam Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[3H]L655708 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Inverse agonist - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[3H]CGS8216 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Mixed - - - no
⤷ [Binds to: benzodiazepine site] agonist and antagonist
Not voltage dependent
[11C]flumazenil Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs - - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
[18F]fluoroethylflumazenil Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - - - - no
⤷ [Binds to: benzodiazepine site]
Not voltage dependent
Allosteric Modulator Comments
Alprazolam is an approved drug which is a positive allosteric modulator of the GABAA receptor. It has affinity for the benzodizepine site on several α subunits.
Triazolam binds to the benzodiazepine binding site of the heteromeric GABAA receptor, binding at the extracellular interface between the α and γ subunits [39]. The drug has been mapped to the relevant, experimental α subunit, and heteromeric partners are listed in the Associated Proteins table above.

Comments based on analysis by Sieghart & Savić (2018) [38]:
α5IA; at concentrations where this compound is an inverse agonist at α5GABAA receptors, it also modulates other receptor subtypes.
L655708 at in vivo concentrations, this compound is only weakly selective.
L838417 is a PAM at α2βγ2, α3βγ2, and α5βγ2 and an antagonist at α1βγ2.
MRK016 and RO4938581 are relatively selective inverse agonists at α5GABAA receptors.
RY024 is selective only at very low concentrations.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]RY80 Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Binding 9.2 pKd 40
⤷ pKd 9.2 (Kd 7x10-10 M) [Binds to: benzodiazepine site] [40]
Tissue Distribution Click here for help
Hippocampus (CA1 stratum pyramidale, CA3 stratum pyramidale)
Expression level:  High
Species:  Rat
Technique:  In situ hybridisation
References:  34,46
Olfactory system (external plexiform layer, accessory olfactory bulb, anterior olfactory nucleus), neocortex (layer 5), subiculum, hippocampus (CA1 stratum pyramidale, CA3, stratum pyramidale, CA3 stratum oriens and radiatum), amygdala (basomedial nucleus posterior part), Septal and basal forebrain region (septohippocampal nucleus), cerebral nuclei (caudatoputamen=striatum, nucleus accumbens), thalamus (paraventricular thalamic nucleus), hypothalamus (auprachiasmatic nucleus, retrochasmatic area, medial tuberal nucleus, lateral mammillary nucleus, infunbdibular stalk), midbrain and pons (red nucleus magnocellular part, dorsal nucleus of the lateral lemniscus, intermediate nucleus of the lateral lemniscus, ventral nucleus of the lateral lemniscus, pontine nuclei, reticulotegmental nucleus of the pons), medulla (inferior olivary complex medial nucleus), cranial nerve nuclei (trigeminal sensory complex principal nucleus, trigeminal senory complex spinal nucleus pars oralis, trigeminal sensory complex spinal nucleus interpolar part, trigeminal sensory complex spinal nucleus caudal part layer 3)
Expression level:  Medium
Species:  Rat
Technique:  Immunohistochemistry
References:  18,35
Olfactory bulb (granule cells), tenia tecta
Expression level:  Medium
Species:  Rat
Technique:  In situ hybridisation
References:  34,46
Neocortex (layer II/III, layer IV, layer V/VI), dentate gyrus granule cells, basal nuclei (claustrum), amygdala (lateral amygdaloid nucleus), septum (bed nucleus of stria terminalis), thalamus (paraventricular nucleus), hypothalamus (medial preoptic area, arcuate nucleus, ventromedial nucleus)
Expression level:  Low
Species:  Rat
Technique:  In situ hybridisation
References:  34,46
Olfactory system (periglomerular cells, internal granular layer), neocortex (layer 6), endopiriform nucleus, parasubiculum, tenia tecta, hippocampus (CA1 stratum oriens and radiatum, CA1, stratum lacunosium-moleculare, amygdala (basolater nucleus), hypothalamus (arcuate nucleus, ventromedial nucleus, tuberomammilary nucleus), midbrain and pons (nucleus of the trapezoid body, superior preolivary nucleus, lateral and medial superior olivary nucleus), cranial nerve nuclei (trigeminal sensory complex spinal nucleus caudal part layers 4 and 5, cochelar nuclei ventral nucleus)
Expression level:  High
Species:  Rat
Technique:  Immunohistochemistry
References:  18,35
Olfactory system (islands of Calleja, olfactory tubercle, nucleus of the lateral olfactory tract), neocortex (layer 1, layers 2-3), insular cortex, perirhinal cortex, piriform cortex (layer 2, layers 1 and 3), entorhinal cortex, presubiculum, dentate gyrus (granular cell layer, molecular layer), amygdala (anterior amygdaloid area, anterior cortical nucleus, central nucleus medial part, central nucleus lateral part, basomedial nucleus anterior part, basolateral nucleu ventral part, lateral nucleus, intercalated nuclei, medial nucleus, posterior cortical nucleus, amygdalohippocampal area), septal and basal forebrain region (lateral septal nucelus dorsal and ventral parts, lateral septal nucleus intermediate part, bed nucleus of the stria terminalis), thalamus (anteroventral nucleus, anteromedial nucleus, intermediodorsal nucleus, rhombioid nucleus), epithalamus (lateral habenular nucleus), subthalamus (zona incerta dorsal part), hypothalamus (anterior preoptic area, lateral hypothalamic area, paraventricular hypothalamic nucleus ventral part, paracventricular hypothalamic nucleus lateral magnocellular part, paraventricular hypothalamic nucleus medial parvocellular part, periventricular nucleus, tuber cinereum area, medium eminence, dorsomedial nucleus, dorsal hypothalamic area, posterior hypothalamic area, paramedian lobule, medial mamillary nucleus medial part, medial mammillary nucleus lateral part, medial mammillary nucleusk posterior part, supramammillary nucleus), midbrain and pons (red nucleus parvocellular part, superior colliculus zonal layer, superior colliculus superficial gray layer, peduncolopontine tegmental nucleus, pontine reticular nucleus oral part, parabrachial nucleus, pontine reticular nucleus caudal part), medulla (medullary reticular nucleus ventral part, inferior olivary complex principal and dorsal nuclei, area postrema), cranial nerve nuclei (oculomotor trochlea nuclei, motor trigeminal nucleus, facial nucleus, ambiguus nucleus, dorsal motor nucleus of the vagus, hypoglossal nucleus, trigeminal sensory complex spinal nucleus caudal part layer 2, cochlear nuclei dorsal nucleus, vestibular nuclei spinal nucleus, solitary tract nuecleus)
Expression level:  Low
Species:  Rat
Technique:  Immunohistochemistry
References:  18,35
Physiological Consequences of Altering Gene Expression Click here for help
Behavioural phenotypes

Mice with a gene knockout of the α5 subunit show an improved performance in a water maze model of sptial learning, whereas the performance in non-hippocampal-dependent learning and in anxiety tasks was unaltered, which is in line with the observation that α5 is mainly expressed in the hippocampus (Collinson et al., 2002). Furthermore, studies with α5 knockout mice revealed that α5-containing GABA(A) receptors mediate the amnestic but not the sedative-hypnotic effects of the general anesthetic etomidate (Cheng et al., 2006). Ethanol impaired fear-conditioning equally in α5 knockout and wild type mice, indicating that α5-containing GABA(A) receptors may not be mediating the memory-blocking properties of ethanol (Martin et al., 2011). In the same study, the α5 knockout mice disploayed higher walking times than wild type mice in the open field at selected doses, potentially pointing to role of α5-containing GABA(A) receptors in the sedative action of ethanol (Martin et al., 2011).
Species:  Mouse
Tissue: 
Technique:  Global knockout of the Gabra5 gene
References:  6,8,29
Electrophysiological phenotypes

In the CA1 region of the hippcocampus the IPSCs were decreased, and paired-pulse facilitation of field EPSPs was enhanced, suggesting that α5-containing GABA(A) receptors play an important role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus (Collinson et al., 2002). These mice also revealed that α5-containing GABA(A) receptors predominatly mediate the tonic inhibitory conductance, and this tonic current is highly sensitive to enhancement by amnestic drugs (Caraiscos et al., 2004a; Glykys et al. 2008) and to low concentrations of isoflurane (Caraiscos et al., 2004b). Field recordings in the CA3 pyramidal layer of α5 knockout mice showed an increased network excitability, suggesting an important role of α5-containing GABA(A) receptors in the control of hippocampal network activity (Glykys et al. 2006). In the α5 knockout mice, the change in power of kainite-induced gamma oscillations (20-80Hz) evoked in CA3 by increasing network drive was greater than in wild type controls, suggesting that α5-containing GABA(A) receptors alter the dynamic profile of of gamma oscillations to changes in network drive (Towers et al., 2004). The depolarizing current required to generate an action potential was found to be two-fold decreased in neurons from α5 knockout mice as compared to neurons from wild type mice, suggesting that α5-containing GABA(A) receptors mediate shunting inhibition that regulates the firing of action potentials (Bonin et al., 2007). Study of the α5 knockout mice also revealed that phasic inhibition mediated by α5-containing GABA(A) receptors is activated by the Schaffer collateral pathway (Vargas-Caballero et al., 2010). The α5 knockout reduces the threshold for induction of LTP (long term potentiation) in a narrow range of stimulus frequencies (10-20Hz) via mechanisms that are predominantly independent of synaptic inhibition; there was no change in baseline membrane potential or input resistance, but increased depolarization during 10Hz stimulation (Martin et al., 2010). This suggests that encoding of hippocampus-dependent memory is regulated by α5-containing GABA(A) receptors und specific conditons that generate moderate but not robusts forms of fear-associated learning (Marin et al., 2010).
Species:  Mouse
Tissue: 
Technique:  Global knockout of the Gabra5 gene
References:  2,4-5,8,20-21,30,42,44
α5 knockout mice have also been shown to display functions in the olivocochlear efferent system: a threshold elevation indicative of outer hair cell dysfunction, and decreased effects of efferent bundle activation, associated with decreased density of efferent terminals on outer hair cells. These degenerative effects suggest that α5-containing GABA(A) receptors play a role in the long-term maintenance of hair cells and neurons in the inner ear (Maison et al., 2006).

After stroke, tonic inhibition mediated by extrasynaptic GABA(A) receptors is increased in the peri-infarct zone though an impairment of GABA transporter (GAT-3/GAT-4) function. In α5 knockout mice, motor recovery was improved, suggesting that the use of α5-specific inverse agonists may be a novel approach to promote recovery after stroke (Clarkson et al., 2010).
Species:  Mouse
Tissue: 
Technique:  Global knockout of the Gabra5 gene
References:  7,28
Behavioral phenotypes

Mice with the H105R point mutation display diazepam-insensitive α5-containing GABA(A) receptors. The muscle relaxaing effect of diazepam is reduced in these mice, but neither the sedative, anticonvulsant, or anxiolytic-like actions of diazepam were impaired (Crestani et al., 2002). Moreover, these mice have been shown to display a reduced expression of the α5 subunit in the hippocampus and are therefore partial α5 knockout mice (Crestani et al., 2002).

In line with the role of the hippocampus in certain forms of associative learning, the hippocampal-dependent trace fear conditioning, but not the hippocampal-independent delay conditioning were altered in these mice (Crestani et al., 2002). In trace fear conditioning, the conditioned stimulus (tone) and the unconditioned stimulus (foot shock) are separated by a time interval, which typically leads to a decrease in response compared to the absence of the time interval in delay fear conditioning. However, this decrease in response is absent in the alpha5(H105R) mice (Yee et al., 2004). Alpha5(H105R) mice were also found to be more resistant to extinction over a three-day period (Yee et al., 2004). Morever, prepulse inhibition of acoustic startle (PPI) was attenuated in alpha5(H105R) mice (Hauser et al., 2005), as was latent inhibition to conditioned taste aversion (Gerdjikov et al., 2008). Alpha5(H105R) mice fail to display tolerance to sedation (van Rijnsoever et al., 2004). In diazepam-tolerant animals only, a reduction in binding of an alpha5-selective radioligand was demonstrated in the dentate gyrus, suggesting that the manifestation of tolerance to the sedative action of diazepam is associated with a downregulation of alpha5-containing GABA(A) receptors in the denate gyrus (van Rijnsoever et al., 2004). Alpha5(H101R) mice display a bias favoring object-based recognition and guidance strategies over spatial processing of objects, i.e. a phenotype indicative of hippocampal dysfunction (Prut et al., 2010).
Species:  Mouse
Tissue: 
Technique:  alpha(H105R) knock-in / partial knockout
References:  11,19,24,36,43,47
Electrophysiological phenotypes

In the hippocampal CA1 region of alpha5(H105R) mice, diazepam increased the amplitude of a small-amplitude subset of spontaneous IPSCs (sIPSCs) (<50 pA) and stimulus-evkoked eIPSCs [GAB(A,slow)] (<300 pA), but in contrast to wild type mice failed to increase the amplitude of larger sIPSCs and eIPSCs. In contrast, diazepam prolonged the decay of GABA(A, fast) sIPSCs as seen in wild type controls. Thus, alpha5-containing GABA(A) receptors contribute to a large-amplitude subset of GABA(A,slow) synpapses, but not to GABA(A,fast) sypnapses (Zarnowska et al., 2009).
Species:  Mouse
Tissue: 
Technique:  alpha(H105R) knock-in / partial knockout
References: 
The Gabra5 gene is located close to the p (pink-eyed dilution) locus in a cluster together with the Gabrg3 and Gabrb3 genes (order: p - Gabrg3, Gabra5, Gabrb3). Compound heterozygotes lacking the Gabra5 and Gabrg3 gene display no overt phenotype, although detailed behavioral analysis was not performed (Culiat et al., 1994). In these mice, the absence of the alpha5 subunit prevents the entire formation of the receptor complex including beta2/3 and gamma2 subunits (Fritschy et al., 1997). The distribution of the alpha2 subunit on the same hippocampal pyramidal neurons that lack the alpha5 subunit in these animals was unchanged, indicating that the assembly of distinct GABA-A receptor subtypes in the same neuron is regulated independently (Fritschy et al., 1998). Deletions that involve the p, Gabrg3, Gabra5 and Gabrb3 genes are assciated with cleft palate (Culiat et al., 1993; Nakatsu et al., 1993), a phenotype which can be rescued by transgenic expression of Gabrb3 (Culiat et al., 1995).
Species:  Mouse
Tissue: 
Technique:  Mapping of p locus chromosomal deletion mutants
References:  12-14,16-17,31
Autism spectrum disorders, Bipolar disorder

Genomic rearrangements involving the GABA-A receptor cluster on chromosome 15 have been found in 1-2% of patients with autism spectrum disorders. Moreover, Gabra5 has been linked to bipolar disorder (Papadimitriou et al., 1998; Otani et al., 2005; Craddock et al., 2010). While Gabra5 has been postulated to be a candidate gene for autism spectrum disorder (Delong, 2007), no convincing evidence for a potential link to these disorders is available.
Species:  Human
Tissue: 
Technique: 
References:  10,15,32-33
General Comments
The α5 subunit is strongly expressed in the hippocampus and deep cortical layers. Evidence suggests that it plays a role in cognitive functions.

References

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1. Albaugh PA, Marshall L, Gregory J, White G, Hutchison A, Ross PC, Gallagher DW, Tallman JF, Crago M, Cassella JV. (2002) Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor. J Med Chem, 45 (23): 5043-51. [PMID:12408715]

2. Bonin RP, Martin LJ, MacDonald JF, Orser BA. (2007) Alpha5GABAA receptors regulate the intrinsic excitability of mouse hippocampal pyramidal neurons. J Neurophysiol, 98 (4): 2244-54. [PMID:17715197]

3. Buettelmann B, Jakob-Roetne R, Knust H, Lucas MC, Thomas A. (2009) Isoxazolo-pyridine derivatives. Patent number: WO2009071476A1. Assignee: Hoffmann-La Roche. Priority date: 04/12/2007. Publication date: 11/06/2009.

4. Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA et al.. (2004) Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci USA, 101 (10): 3662-7. [PMID:14993607]

5. Caraiscos VB, Newell JG, You-Ten KE, Elliott EM, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. (2004) Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane. J Neurosci, 24 (39): 8454-8. [PMID:15456818]

6. Cheng VY, Martin LJ, Elliott EM, Kim JH, Mount HT, Taverna FA, Roder JC, Macdonald JF, Bhambri A, Collinson N et al.. (2006) Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J Neurosci, 26 (14): 3713-20. [PMID:16597725]

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