Protein / target
Neuronal acetylcholine receptor subunit alpha-4
Protein at a glance
Biological role
Acetylcholine-gated monoatomic cation-selective channel activity
Primary system
Nervous system
Strongest disease association
autosomal dominant nocturnal frontal lobe epilepsy
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
3 approved · 12 in clinical development
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
Function
Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate synaptic transmission in the nervous system and the neuromuscular junction. Each nAchR subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, cation permeability, and binding to allosteric modulators (PubMed:22361591, PubMed:27698419, PubMed:29720657, PubMed:38454578). CHRNA4 forms heteropentameric neuronal acetylcholine receptors with CHRNB2 and CHRNB4, as well as CHRNA5 and CHRNB3 as accesory subunits. Is the most abundant nAChR subtype expressed in the central nervous system (PubMed:16835356, PubMed:22361591, PubMed:27698419, PubMed:29720657, PubMed:38454578). Found in two major stoichiometric forms,(CHRNA4)3:(CHRNB2)2 and (CHRNA4)2:(CHRNB2)3, the two stoichiometric forms differ in their unitary conductance, calcium permeability, ACh sensitivity and potentiation by divalent cation (PubMed:27698419, PubMed:29720657, PubMed:38454578). Involved in the modulation of calcium-dependent signaling pathways, influences the release of neurotransmitters, including dopamine, glutamate and GABA (By similarity)
Subcellular location
Domains and Gene Ontology detail (40)Hide
Gene Ontology
- Cacetylcholine-gated channel complex
- Ccation channel complex
- Cdendrite
- Cexternal side of plasma membrane
- Cmembrane
- Cneuron projection
- Cneuronal cell body
- Cneurotransmitter receptor complex
- Cplasma membrane
- Cpostsynaptic membrane
- Cpresynaptic membrane
- Csynapse
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Synaptic signalling
- ·Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, liga…
- ·neurotransmitter receptor complex
- ·postsynaptic membrane
- ·presynaptic membrane
Ligand-gated signalling
- ·Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, liga…
- ·ligand-gated monoatomic ion channel activity
Ion channel gating
- ·acetylcholine-gated channel complex
- ·ligand-gated monoatomic ion channel activity
- ·monoatomic ion transmembrane transport
Inhibitory neurotransmission
- ·inhibitory postsynaptic potential
Immune signalling
- ·B cell activation
View underlying pathways (3)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
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.
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
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.
Neuronal acetylcholine receptor; alpha4/beta2 agonist
Appears in clinical studies involving nicotine dependence, non-small cell lung carcinoma, smoking cessation, nicotine dependence
Neuronal acetylcholine receptor; alpha4/beta2 antagonist
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
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.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 502 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 · 16 total
irritable bowel syndrome · dry eye syndrome · gastroparesis
Cognitive impairment
anxiety disorder · attention deficit-hyperactivity disorder · dementia
major depressive disorder · overactive bladder · Hyperhidrosis
nicotine dependence · non-small cell lung carcinoma · smoking cessation
smoking behavior · pregnancy · nicotine dependence
smoking cessation · nicotine dependence · ventricular tachycardia
nicotine dependence
gastrointestinal disease · major depressive disorder
Alzheimer disease · schizophrenia · Alzheimer disease
Tractability
Safety liabilities
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Forefront confidence
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.
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
Recent activity around this target, drawn from one canonical event stream. Every item is reached through 2 drugs that target this protein, so each event is news about that drug rather than about the protein directly.
- Regulatory actionFDA authorized Zyn nicotine pouches without knowing what they were made of, says former agency scientist
- Industry developmentShould nicotine be regulated like a narcotic? A Pacific nation makes the case
- New publicationElectronic cigarettes and cardiovascular disease: epidemiological and biological links.
- New publicationA Pilot Randomized Trial of Transdermal Nicotine for Pulmonary Sarcoidosis.
- New publicationDesign, rationale, and baseline characteristics of a pilot randomized clinical trial of nicotine treatment for pulmonary sarcoidosis.
- New publicationNicotine replacement therapy for smoking cessation.
- New publicationNicotine related brain activity: the influence of smoking history and blood nicotine levels, an exploratory study.
- New publicationEffects of transdermal nicotine on symptoms, moods, and cardiovascular activity in the everyday lives of smokers and nonsmokers with attention-deficit/hyperactivity disorder.
- New publicationPicomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus.
- New publicationThe brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications.
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.