Protein / target

Gamma-aminobutyric acid receptor subunit alpha-5

GABRA5P31644Homo sapiensSwiss-Prot
UniProt: P31644Ensembl: ENSG00000186297HGNC: HGNC:4079NCBI Gene: 2558
Clinically validated
Therapeutic maturity
58
Approved medicines
30
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

GABA-gated chloride ion channel activity

Primary system

Nervous system

Strongest disease association

genetic developmental and epileptic encephalopathy

Genetic evidence · score 0.83

Therapeutic maturity

Clinically validated target

58 approved medicines against this target

Druggability

Small molecule

Open Targets tractability · Approved Drug

Clinical development

58 approved · 9 in clinical development

30 linked trials

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:14993607, PubMed:29961870, PubMed:30140029, PubMed:31056671). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:30140029). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:14993607, PubMed:30140029). GABAARs containing alpha-5/GABRA5 subunits are mainly extrasynaptic and contribute to the tonic GABAergic inhibition in the hippocampus (By similarity). Extrasynaptic alpha-5-containing GABAARs in CA1 pyramidal neurons play a role in learning and memory processes (By similarity)

Subcellular location

Postsynaptic cell membraneCell membrane
Domains and Gene Ontology detail (23)

Gene Ontology

  • Cchloride channel complex
  • Cdendrite membrane
  • CGABA-A receptor complex
  • CGABA-ergic synapse
  • Cneuronal cell body membrane
  • Cplasma membrane
  • Cpostsynapse
  • Cpostsynaptic specialization membrane
  • Cpresynaptic membrane
  • FGABA receptor binding
  • FGABA-A receptor activity
  • FGABA-gated chloride ion channel activity

462 aa · 52 kDa

Biological roles

Reactome v97

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Inhibitory neurotransmissionUniProt · GOSynaptic signallingUniProt · GOChloride transportUniProt · GOLigand-gated signallingUniProt · GOIon channel gatingGO
View supporting evidence

Inhibitory neurotransmission

  • ·Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-amino…
  • ·GABA-ergic synapse
  • ·inhibitory synapse assembly
  • ·synaptic transmission, GABAergic

Synaptic signalling

  • ·Postsynaptic cell membrane
  • ·GABA-ergic synapse
  • ·postsynapse
  • ·postsynaptic specialization membrane

Chloride transport

  • ·Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-amino…
  • ·chloride channel complex
  • ·GABA-gated chloride ion channel activity

Ligand-gated signalling

  • ·Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-amino…
  • ·ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membr…
  • ·transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic…

Ion channel gating

  • ·GABA-gated chloride ion channel activity
  • ·ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membr…
  • ·transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic…
View underlying pathways (1)
GABA receptor activation

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Interaction neighbourhood

STRING v12.0

Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.

TRAK2PLCL1NSFHAP1SLC6A1GABRA3GABBR1GABBR2GABRB1SLC6A13GABRA5

10 strongest partners — larger node and heavier line mean higher confidence

Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.

Drugs targeting this protein

4

Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.

Midazolam
ApprovedPositive allosteric modulator

GABA-A receptor; anion channel positive allosteric modulator

Appears in clinical studies involving epilepsy, status epilepticus, Irritability, post-traumatic stress disorder

Acts on a complex — shared with GABRG2, GABRB3, GABRG3 +12 more · 1 of 16 recorded protein targets — broad pharmacology

Isoflurane
ApprovedPositive allosteric modulator

GABA-A receptor; anion channel positive allosteric modulator

Appears in clinical studies involving kidney injury, Hydrocephalus, delirium, sedation

Acts on a complex — shared with GABRG2, GABRB3, GABRG3 +12 more · 1 of 23 recorded protein targets — broad pharmacology

Halothane
ApprovedPositive allosteric modulator

GABA-A receptor; anion channel positive allosteric modulator

Appears in clinical studies involving septic shock, Sepsis

Acts on a complex — shared with GABRG2, GABRB3, GABRG3 +12 more · 1 of 23 recorded protein targets — broad pharmacology

sevoflurane
ApprovedPositive allosteric modulator

GABA-A receptor; anion channel positive allosteric modulator

Appears in clinical studies involving endometrial cancer, myocardial infarction, sedation, delirium

Acts on a complex — shared with GABRG2, GABRB3, GABRG3 +12 more · 1 of 23 recorded protein targets — broad pharmacology

ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.

Translational evidence

Open Targets 26

Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.

Strongest genetic associations

Human genetic evidence — the most direct causal link between this target and a disease.

genetic developmental and epileptic encephalopathy0.83

Genetic · overall 0.63

Seizure0.19

Genetic · overall 0.62

Highest-confidence therapeutic associations

Diseases where a drug acting on this target has already reached clinical development.

insomnia1.00

Clinical · overall 0.61

migraine disorder1.00

Clinical · overall 0.61

epilepsy1.00

Clinical · overall 0.61

major depressive disorder0.99

Clinical · overall 0.61

panic disorder0.99

Clinical · overall 0.61

Highest overall evidence

Remaining associations by Open Targets' aggregated evidence score.

Anxiety0.60

Clinical

anxiety disorder0.60

Clinical

Agitation0.60

Clinical

Show all associations
genetic developmental and epileptic encephalopathy0.63
Seizure0.62
epilepsy0.61
major depressive disorder0.61
migraine disorder0.61
panic disorder0.61
insomnia0.61
Anxiety0.60
anxiety disorder0.60
Agitation0.60

Open Targets ranks 1,426 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.

Known drugs · 72 total

GANAXOLONEApproval

Seizure · epilepsy syndrome · infantile spasms

DIAZEPAMApproval

Agitation · epilepsy · anxiety disorder

ADIPIPLONPhase 2

sleep-wake disorder · insomnia

BREXANOLONEApproval

postpartum depression · depressive disorder · major depressive disorder

MIDAZOLAM HYDROCHLORIDEApproval

amnesia · Seizure · status epilepticus

REMIMAZOLAM BESYLATEApproval

sedation · Loss of consciousness · Hypoxemia

CLOBAZAMApproval

Lennox-Gastaut syndrome · Seizure · anxiety disorder

ENFLURANEApproval

septic shock · Sepsis

SECOBARBITALApproval
FLURAZEPAMApproval

insomnia

Tractability

SM · Approved DrugSM · Structure with LigandSM · High-Quality LigandSM · Druggable FamilyAB · UniProt loc high confAB · GO CC high confAB · UniProt SigP or TMHMMAB · Human Protein Atlas locPR · UniProt UbiquitinationPR · Database UbiquitinationPR · Half-life DataPR · Small Molecule Binder

Safety liabilities

decreased cardiac contractilitydecreased memorydecreased convulsionsdecreased locomotor activityincreased sleepincreased eatingincreased respiratory ratedecreased sleepmuscle relaxationdecreased body temperaturedecreased paindecreased blood pressure

Clinical trials

30

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.

Double-blind Randomized Controlled Trial of Caudal Versus Intravenous Dexmedetomidine for Supplementation of Caudal Analgesia in ChildrenPHASE2

COMPLETED · via sevoflurane · NCT01701778

Two-part, Double-blind, Placebo-controlled, Randomized, Parallel-group Study: (Part 1) in Healthy Male Subjects to Assess Safety and Tolerability of Ascending Repeated Oral Doses of BAY1902607 Including Its Effect on the Pharmacokinetics of a Sub-therapeutic Dose of Midazolam (MDZ), Followed by (Part 2) a Two-way Crossover Administration of Four Different Doses of BAY1902607 in Patients With Refractory Chronic Cough to Assess Safety, Tolerability and Efficacy for Proof of ConceptPHASE1/PHASE2

COMPLETED · via Midazolam · NCT03535168

The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam, a Cytochrome P450 3A4/P-gp (CYP3A4) Substrate, in Postmenopausal Osteoporotic WomenPHASE1

COMPLETED · via Midazolam · NCT01221727

Anaesthesia With Propofol Versus Midazolam : Effect on Oxidative Stress in the Brain of Head Trauma PatientsPHASE3

TERMINATED · via Midazolam · NCT00336882

Safety, Tolerability and Pharmacokinetics of Single and Multiple Oral Doses of BI 3031185 in Japanese Healthy Male Trial Participants (Single-blind, Randomised, Placebo-controlled, Parallel Group Design) and Effect of Multiple Doses of BI 3031185 on Pharmacokinetics of a Single Dose of a Combination of Drospirenone and Ethinylestradiol (Oral Contraceptive) in Japanese Healthy Female Trial Participants (Non-randomised, Open-label, Fixed Sequence Design)PHASE1

NOT_YET_RECRUITING · via Midazolam · NCT07656792

A Study on the Relationship Between Biodiversity of Intestinal Microbiota in Patients and Different Sedative-hypnotics Undergoing Mechanical VentilationNA

WITHDRAWN · via Midazolam · NCT03401736

Show remaining trials (24)
Anesthesia With Sevoflurane and Isoflurane for Excision Surgeries in Benign Breast TumorsPHASE4

COMPLETED · via sevoflurane · NCT00575354

A Pilot Study of the Effects of Nebulized Epoprostenol (Flolan) and Systemic Phenylephrine on Arterial Oxygenation During One Lung VentilationPHASE4

COMPLETED · via sevoflurane · NCT02748265

Resveratrol and Midazolam MetabolismNA

COMPLETED · via Midazolam · NCT01173640

Sedation and Analgesia for Transjugular Liver Biopsy: A Randomized Double Blind Placebo Controlled TrialPHASE4

COMPLETED · via Midazolam · NCT00596414

A Phase 1, Open-Label, Single-Center, 2-Period, Single-Sequence Drug-Drug Interaction Study to Evaluate the Effects of Multiple-Dose Telotristat Etiprate on the Pharmacokinetics of Single-Dose Midazolam, a Sensitive P450-3A4 Substrate, in Healthy Male and Female SubjectsPHASE1

COMPLETED · via Midazolam · NCT02147808

Pilot Study of Spinal Manipulation for Chronic Neck PainPHASE1

TERMINATED · via Midazolam · NCT00030004

Effect of Midazolam on Inflammatory Response and Organ Function in Mechanically Ventilated Sepsis Patients With Different Immune Status.PHASE4

UNKNOWN · via Midazolam · NCT02135055

The Effect of Sevoflurane and Desflurane Anesthetic Agents Used in Elective Cholecystectomy Surgery on Heme Oxygenase-1 mRNA Expression and Heme Oxygenase-1 Protein Levels: A Comparative Prospective StudyPHASE4

WITHDRAWN · via sevoflurane · NCT06457958

Dexmedetomidine Versus Sevoflurane Inhalation for Fibreoptic Nasotracheal Intubation in Children With Anticipated Difficult IntubationPHASE2

UNKNOWN · via sevoflurane · NCT04426552

Safety, Tolerability, and Pharmacokinetics of Multiple Rising Oral Doses of BI 706321 in Healthy Male and Female Subjects (Doubleblind, Randomised, Placebo-controlled, Parallel Group Design)PHASE1

COMPLETED · via Midazolam · NCT04241458

Bispectral Index Guiding Etomidate Used in Children Aged 3 to 10 for Clinical Anesthesia InductionPHASE4

UNKNOWN · via sevoflurane · NCT02182648

The Effects of Different Anesthetic Techniques on QT, Corrected QT (QTc), and P Wave Dispersions in Cesarean SectionPHASE4

COMPLETED · via sevoflurane · NCT03134677

AN OPEN-LABEL PHASE 1 STUDY TO EVALUATE PF-07994525 IN PARTICIPANTS WITH ADVANCED MALIGNANCIESPHASE1

RECRUITING · via Midazolam · NCT07426757

Minimal Alveolar Concentration of Sevoflurane Inducing Isoelectric ElectroencephalogramPHASE4

COMPLETED · via sevoflurane · NCT01662622

Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and StatinsNA

COMPLETED · via sevoflurane · NCT00995670

Evaluation of the Analgesic Effect of Midazolam and Ketamine as an Additive to Intrathecal Bupivacaine in Patients Undergoing Cesarean SectionPHASE1/PHASE2

COMPLETED · via Midazolam · NCT01404442

Sevoflurane vs Propofol Effect on Endothelial Damage Markers After Knee Ligament Surgery. A Randomized Controlled TrialNA

COMPLETED · via sevoflurane · NCT03772054

A Phase 1, Open Label, Fixed Sequence Study to Evaluate the Effect of ECC5004 on the Single Dose Pharmacokinetics of Atorvastatin, Rosuvastatin, Digoxin and Midazolam in Healthy ParticipantsPHASE1

COMPLETED · via Midazolam · NCT06293742

The Effect of Etomidate on Outcomes of Trauma PatientsNA

WITHDRAWN · via Midazolam · NCT00938990

Post Anesthesia Emergence and Behavioral Changes in Children Undergoing MRI: Comparative Study Using Propofol, Sevoflurane and IsofluranePHASE4

TERMINATED · via sevoflurane · NCT02111447

A Phase I, Randomized, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 581 in Healthy Subjects or Subjects With Schizophrenia or Schizoaffective Disorder on Antipsychotic MedicationPHASE1

COMPLETED · via Midazolam · NCT02504476

Comparison Between Continuous Infusion and Intermittent Bolus Injection of Propofol for Deep Sedation During Endoscopic Retrograde Cholangiopancreatography: a Prospective Randomized Controlled StudyNA

UNKNOWN · via Midazolam · NCT01900938

Quadratus Lumborum Versus Transversus Abdominis Plane Block Versus Caudal Block for Postoperative Analgesia After Pediatric Inguinal Hernia : Double-Blinded Randomized TrialNA

UNKNOWN · via sevoflurane · NCT05442905

An Open-Label, Single-Sequence Study to Evaluate the Potential CYP 3A4 Pharmacokinetic Interaction of GW876008 in Healthy SubjectsPHASE1

COMPLETED · via Midazolam · NCT00423761

ClinicalTrials.gov via the drug-target graph.

Forefront confidence

Synthesis

Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.

genetic developmental and epileptic encephalopathyWell supported
0.87
agreement 0.75–0.99
Genetic80%Animal model20%Literature0%Genetic literaturedup

Open Targets aggregate 0.63 · 3 independent evidence families · 1 not counted as duplicate

SeizureWell supported
0.78
agreement 0.68–0.89
Clinical78%Genetic21%Literature1%

Open Targets aggregate 0.62 · 3 independent evidence families

epilepsyWell supported
0.75
agreement 0.60–0.91
Clinical97%Literature3%

Open Targets aggregate 0.61 · 2 independent evidence families

major depressive disorderWell supported
0.75
agreement 0.59–0.91
Clinical98%Literature2%

Open Targets aggregate 0.61 · 2 independent evidence families

migraine disorderModerately supported
0.75
agreement 0.59–0.90
Clinical100%Literature0%

Open Targets aggregate 0.61 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.

What's happening now

13

Recent activity around this target, drawn from one canonical event stream. Every item is reached through 3 drugs that target this protein, so each event is news about that drug rather than about the protein directly.

  1. Trial status changed2026-07-20

    A Phase 1 Study to Evaluate the Effect of Multiple Doses of ABBV-722 on the Pharmacokinetics of Cocktail Probe Substrates of CYP3A and Select Transporters in Healthy Adult Subjects

    Status changed to Active, not recruiting · ClinicalTrials.gov · via Midazolam

  2. New publication2025-02-08
    Neonatal sevoflurane exposures inhibits DHHC5-mediated palmitoylation of TfR1 in oligodendrocytes, leading to hypomyelination and neurological impairments.

    Journal of advanced research · 2025 · 9 citations · Europe PMC · via sevoflurane

  3. New publication2024-01-17
    Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.

    The Journal of pharmacology and experimental therapeutics · 2024 · 14 citations · Europe PMC · via Midazolam

  4. New publication2024-01-17
    Sex Differences in Organophosphate Model of Benzodiazepine-Refractory Status Epilepticus and Neuronal Damage.

    The Journal of pharmacology and experimental therapeutics · 2024 · 12 citations · Europe PMC · via Midazolam

  5. New publication2019-09-26
    First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound.

    Nature communications · 2019 · 366 citations · Europe PMC · via Midazolam

  6. New publication2018-10-04
    Safety and Efficacy of Remimazolam Compared With Placebo and Midazolam for Moderate Sedation During Bronchoscopy.

    Chest · 2019 · 220 citations · Europe PMC · via Midazolam

  7. New publication2018-04-30
    A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy.

    Gastrointestinal endoscopy · 2018 · 209 citations · Europe PMC · via Midazolam

  8. New publication2015-04-01
    A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy.

    Anesthesia and analgesia · 2015 · 151 citations · Europe PMC · via Midazolam

  9. New publication2011-10-01
    A randomized clinical trial comparing oral, aerosolized intranasal, and aerosolized buccal midazolam.

    Annals of emergency medicine · 2011 · 49 citations · Europe PMC · via Midazolam

  10. Regulatory approval2011-09-04

    Approval: Buccolam (EMA)

    ema · regulatory · ema · via Midazolam

  11. New publication2010-09-15
    A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study.

    Annals of emergency medicine · 2010 · 47 citations · Europe PMC · via Midazolam

  12. New publication2003-02-01
    Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.

    The Journal of neuroscience : the official journal of the Society for Neuroscience · 2003 · 1,387 citations · Europe PMC · via Midazolam

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.