UniProt functional annotation for O75899



	UniProt functional annotation for O75899

UniProt code: O75899.

Organism: Homo sapiens (Human).

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

Function: Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10075644, PubMed:10773016, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644, PubMed:9872744, PubMed:10906333, PubMed:10773016). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872744, PubMed:22660477). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:9872316, PubMed:10075644, PubMed:9872744, PubMed:22660477). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable). {ECO:0000269|PubMed:10075644, ECO:0000269|PubMed:10328880, ECO:0000269|PubMed:15617512, ECO:0000269|PubMed:18165688, ECO:0000269|PubMed:22660477, ECO:0000269|PubMed:24305054, ECO:0000269|PubMed:9872316, ECO:0000269|PubMed:9872744, ECO:0000305}.

Subunit: Heterodimer of GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:10906333, PubMed:10773016, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Homodimers may form, but are inactive (PubMed:15617512). Interacts (via C-terminus) with ATF4 (via leucine zipper domain) (By similarity). {ECO:0000250|UniProtKB:Q9Z0U4, ECO:0000269|PubMed:10773016, ECO:0000269|PubMed:15617512, ECO:0000269|PubMed:18165688, ECO:0000269|PubMed:22660477, ECO:0000269|PubMed:24305054, ECO:0000269|PubMed:9872316, ECO:0000269|PubMed:9872744}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:10328880, ECO:0000269|PubMed:15617512, ECO:0000269|PubMed:9872316}; Multi-pass membrane protein {ECO:0000305}. Cell junction, synapse, postsynaptic cell membrane {ECO:0000250|UniProtKB:O88871}; Multi-pass membrane protein {ECO:0000305}. Note=Coexpression of GABBR1 and GABBR2 is required for GABBR1 maturation and transport to the plasma membrane. In contrast, GABBR2 does not depend on GABBR1 for transport to the cell membrane. {ECO:0000269|PubMed:15617512}.

Tissue specificity: Highly expressed in brain, especially in cerebral cortex, thalamus, hippocampus, frontal, occipital and temporal lobe, occipital pole and cerebellum, followed by corpus callosum, caudate nucleus, spinal cord, amygdala and medulla (PubMed:10087195, PubMed:10328880, PubMed:10727622, PubMed:9872744). Weakly expressed in heart, testis and skeletal muscle (PubMed:10087195, PubMed:10727622). {ECO:0000269|PubMed:10087195, ECO:0000269|PubMed:10328880, ECO:0000269|PubMed:10727622, ECO:0000269|PubMed:9872744}.

Domain: Alpha-helical parts of the C-terminal intracellular region mediate heterodimeric interaction with GABBR1. {ECO:0000305|PubMed:9872744}.

Disease: Neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) [MIM:617903]: An autosomal dominant disorder characterized by psychomotor developmental stagnation or regression. NDPLHS manifest in the first years of life as loss of purposeful hand movements, loss of language, and intellectual disability. {ECO:0000269|PubMed:26740508, ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29369404}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Developmental and epileptic encephalopathy 59 (DEE59) [MIM:617904]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE59 is an autosomal dominant condition characterized by onset of refractory seizures in early infancy. {ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29100083, ECO:0000269|PubMed:29369404}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the G-protein coupled receptor 3 family. GABA-B receptor subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAH35071.2; Type=Erroneous initiation; Evidence={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:		Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10075644, PubMed:10773016, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644, PubMed:9872744, PubMed:10906333, PubMed:10773016). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872744, PubMed:22660477). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:9872316, PubMed:10075644, PubMed:9872744, PubMed:22660477). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable). {ECO:0000269\|PubMed:10075644, ECO:0000269\|PubMed:10328880, ECO:0000269\|PubMed:15617512, ECO:0000269\|PubMed:18165688, ECO:0000269\|PubMed:22660477, ECO:0000269\|PubMed:24305054, ECO:0000269\|PubMed:9872316, ECO:0000269\|PubMed:9872744, ECO:0000305}.


Subunit:		Heterodimer of GABBR1 and GABBR2 (PubMed:9872316, PubMed:9872744, PubMed:10906333, PubMed:10773016, PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054). Homodimers may form, but are inactive (PubMed:15617512). Interacts (via C-terminus) with ATF4 (via leucine zipper domain) (By similarity). {ECO:0000250\|UniProtKB:Q9Z0U4, ECO:0000269\|PubMed:10773016, ECO:0000269\|PubMed:15617512, ECO:0000269\|PubMed:18165688, ECO:0000269\|PubMed:22660477, ECO:0000269\|PubMed:24305054, ECO:0000269\|PubMed:9872316, ECO:0000269\|PubMed:9872744}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:10328880, ECO:0000269\|PubMed:15617512, ECO:0000269\|PubMed:9872316}; Multi-pass membrane protein {ECO:0000305}. Cell junction, synapse, postsynaptic cell membrane {ECO:0000250\|UniProtKB:O88871}; Multi-pass membrane protein {ECO:0000305}. Note=Coexpression of GABBR1 and GABBR2 is required for GABBR1 maturation and transport to the plasma membrane. In contrast, GABBR2 does not depend on GABBR1 for transport to the cell membrane. {ECO:0000269\|PubMed:15617512}.
Tissue specificity:		Highly expressed in brain, especially in cerebral cortex, thalamus, hippocampus, frontal, occipital and temporal lobe, occipital pole and cerebellum, followed by corpus callosum, caudate nucleus, spinal cord, amygdala and medulla (PubMed:10087195, PubMed:10328880, PubMed:10727622, PubMed:9872744). Weakly expressed in heart, testis and skeletal muscle (PubMed:10087195, PubMed:10727622). {ECO:0000269\|PubMed:10087195, ECO:0000269\|PubMed:10328880, ECO:0000269\|PubMed:10727622, ECO:0000269\|PubMed:9872744}.
Domain:		Alpha-helical parts of the C-terminal intracellular region mediate heterodimeric interaction with GABBR1. {ECO:0000305\|PubMed:9872744}.
Disease:		Neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) [MIM:617903]: An autosomal dominant disorder characterized by psychomotor developmental stagnation or regression. NDPLHS manifest in the first years of life as loss of purposeful hand movements, loss of language, and intellectual disability. {ECO:0000269\|PubMed:26740508, ECO:0000269\|PubMed:28856709, ECO:0000269\|PubMed:29369404}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Developmental and epileptic encephalopathy 59 (DEE59) [MIM:617904]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE59 is an autosomal dominant condition characterized by onset of refractory seizures in early infancy. {ECO:0000269\|PubMed:28856709, ECO:0000269\|PubMed:29100083, ECO:0000269\|PubMed:29369404}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the G-protein coupled receptor 3 family. GABA-B receptor subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAH35071.2; Type=Erroneous initiation; Evidence={ECO:0000305};