UniProt functional annotation for P14867



	UniProt functional annotation for P14867

UniProt code: P14867.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, 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 alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:23909897, PubMed:25489750). GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity). {ECO:0000250|UniProtKB:P62812, ECO:0000250|UniProtKB:P62813, ECO:0000269|PubMed:23909897, ECO:0000269|PubMed:25489750, ECO:0000269|PubMed:29950725}.

Activity regulation: Allosterically activated by benzodiazepines and the anesthetic alphaxalone (PubMed:30266951, PubMed:29950725). Allosterically activated by pentobarbital (By similarity). Inhibited by the antagonist bicuculline (PubMed:29950725). {ECO:0000250|UniProtKB:P62813, ECO:0000269|PubMed:29950725, ECO:0000269|PubMed:30266951}.

Subunit: Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:29950725, PubMed:30266951). Interacts with UBQLN1 (By similarity). Interacts with TRAK1 (By similarity). Interacts with KIF21B (By similarity). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity). Interacts with LHFPL4 (PubMed:28978485, PubMed:29742426). Interacts with NLGN2 (By similarity). Interacts with SHISA7; interaction leads regulation of GABA(A) receptor trafficking, channel deactivation kinetics and pharmacology (By similarity). {ECO:0000250|UniProtKB:P62812, ECO:0000250|UniProtKB:P62813, ECO:0000269|PubMed:28978485, ECO:0000269|PubMed:29742426, ECO:0000269|PubMed:29950725, ECO:0000269|PubMed:30266951}.

Subcellular location: Cell junction, synapse, postsynaptic cell membrane {ECO:0000250|UniProtKB:P08219}; Multi-pass membrane protein {ECO:0000255}. Cell membrane {ECO:0000269|PubMed:2465923}; Multi-pass membrane protein {ECO:0000255}. Cytoplasmic vesicle membrane {ECO:0000250|UniProtKB:P62813}.

Domain: The extracellular domain contributes to synaptic contact formation. {ECO:0000250|UniProtKB:P62812}.

Ptm: Glycosylated. {ECO:0000250|UniProtKB:P62812}.

Disease: Epilepsy, childhood absence 4 (ECA4) [MIM:611136]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:16718694}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Epilepsy, idiopathic generalized 13 (EIG13) [MIM:611136]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:21714819}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Juvenile myoclonic epilepsy 5 (EJM5) [MIM:611136]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269|PubMed:11992121}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Developmental and epileptic encephalopathy 19 (DEE19) [MIM:615744]: A severe neurologic disorder characterized by onset of seizures in the first months of life and usually associated with EEG abnormalities. Affected infants have convulsive seizures (hemiclonic or generalized) that are often prolonged and triggered by fever. Other seizure types include focal, myoclonic, absence seizures, and drop attacks. Development is normal in the first year of life with later slowing and intellectual disability. {ECO:0000269|PubMed:24623842, ECO:0000269|PubMed:27864847}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA1 sub- subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, 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 alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:23909897, PubMed:25489750). GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity). {ECO:0000250\|UniProtKB:P62812, ECO:0000250\|UniProtKB:P62813, ECO:0000269\|PubMed:23909897, ECO:0000269\|PubMed:25489750, ECO:0000269\|PubMed:29950725}.


Activity regulation:		Allosterically activated by benzodiazepines and the anesthetic alphaxalone (PubMed:30266951, PubMed:29950725). Allosterically activated by pentobarbital (By similarity). Inhibited by the antagonist bicuculline (PubMed:29950725). {ECO:0000250\|UniProtKB:P62813, ECO:0000269\|PubMed:29950725, ECO:0000269\|PubMed:30266951}.
Subunit:		Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:29950725, PubMed:30266951). Interacts with UBQLN1 (By similarity). Interacts with TRAK1 (By similarity). Interacts with KIF21B (By similarity). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (By similarity). Interacts with LHFPL4 (PubMed:28978485, PubMed:29742426). Interacts with NLGN2 (By similarity). Interacts with SHISA7; interaction leads regulation of GABA(A) receptor trafficking, channel deactivation kinetics and pharmacology (By similarity). {ECO:0000250\|UniProtKB:P62812, ECO:0000250\|UniProtKB:P62813, ECO:0000269\|PubMed:28978485, ECO:0000269\|PubMed:29742426, ECO:0000269\|PubMed:29950725, ECO:0000269\|PubMed:30266951}.
Subcellular location:		Cell junction, synapse, postsynaptic cell membrane {ECO:0000250\|UniProtKB:P08219}; Multi-pass membrane protein {ECO:0000255}. Cell membrane {ECO:0000269\|PubMed:2465923}; Multi-pass membrane protein {ECO:0000255}. Cytoplasmic vesicle membrane {ECO:0000250\|UniProtKB:P62813}.
Domain:		The extracellular domain contributes to synaptic contact formation. {ECO:0000250\|UniProtKB:P62812}.
Ptm:		Glycosylated. {ECO:0000250\|UniProtKB:P62812}.
Disease:		Epilepsy, childhood absence 4 (ECA4) [MIM:611136]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269\|PubMed:16718694}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Epilepsy, idiopathic generalized 13 (EIG13) [MIM:611136]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. {ECO:0000269\|PubMed:21714819}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Juvenile myoclonic epilepsy 5 (EJM5) [MIM:611136]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269\|PubMed:11992121}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Developmental and epileptic encephalopathy 19 (DEE19) [MIM:615744]: A severe neurologic disorder characterized by onset of seizures in the first months of life and usually associated with EEG abnormalities. Affected infants have convulsive seizures (hemiclonic or generalized) that are often prolonged and triggered by fever. Other seizure types include focal, myoclonic, absence seizures, and drop attacks. Development is normal in the first year of life with later slowing and intellectual disability. {ECO:0000269\|PubMed:24623842, ECO:0000269\|PubMed:27864847}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA1 sub- subfamily. {ECO:0000305}.