GABA transporter 2 (GAT2, also known as GAT-2) is a sodium-dependent GABA transporter belonging to the SLC6A family. While GAT1 is the predominant GABA transporter in the brain, GAT2 plays important roles in peripheral tissues and contributes to GABA homeostasis in specific brain regions.
Gene Overview
The SLC6A13 gene encodes GAT2, producing a protein of 602 amino acids with 12 transmembrane domains. Unlike GAT1 (SLC6A1), GAT2 has distinct pharmacological properties and tissue distribution. The gene is located on chromosome 12p12.3 and consists of 14 exons. [@guastella1992]
Structure and Mechanism
GAT2 shares the core structural features of SLC6A family transporters: [@borden1994]
12 transmembrane helices forming the translocation pore
Sodium and chloride dependence for transport activity
N-glycosylation sites on extracellular loops affecting trafficking
GABA transporter 2 (GAT2, also known as GAT-2) is a sodium-dependent GABA transporter belonging to the SLC6A family. While GAT1 is the predominant GABA transporter in the brain, GAT2 plays important roles in peripheral tissues and contributes to GABA homeostasis in specific brain regions.
Gene Overview
The SLC6A13 gene encodes GAT2, producing a protein of 602 amino acids with 12 transmembrane domains. Unlike GAT1 (SLC6A1), GAT2 has distinct pharmacological properties and tissue distribution. The gene is located on chromosome 12p12.3 and consists of 14 exons. [@guastella1992]
Structure and Mechanism
GAT2 shares the core structural features of SLC6A family transporters: [@borden1994]
12 transmembrane helices forming the translocation pore
Sodium and chloride dependence for transport activity
N-glycosylation sites on extracellular loops affecting trafficking
GAT2 has lower affinity for GABA compared to GAT1 (Km ~50 μM vs ~5 μM for GAT1) and exhibits different substrate specificities for pharmacological agents. The transport cycle involves: [@kanner1983]
Sodium binding to the transporter
GABA binding at the extracellular face
Conformational change exposing substrate to intracellular side
Release of sodium and GABA
Return to extracellular-facing conformation
Expression Pattern
GAT2 expression differs from GAT1: [@minelli1996]
Liver: Highest expression in periportal hepatocytes
Glial cells ([astrocytes](/entities/astrocytes) and microglia)
Peripheral expression is much higher than central nervous system expression. In the brain, GAT2 is considered a minor GABA transporter but serves important functions in specific niches. [@conti1999]
Physiological Role
Peripheral Tissues
In liver and kidney, GAT2 contributes to: [@decavel1997]
GABA metabolism and ammonia detoxification: GABA is metabolized via GABA-shunt pathway
The liver expresses high levels of GAT2 where it participates in the GABA-shunt, linking GABA metabolism to the urea cycle and ammonia detoxification. [@richerson2001]
Brain
In regions where expressed, GAT2: [@schousboe2003]
Modulates extracellular GABA levels
Contributes to glial GABA clearance
May play roles in neuroendocrine regulation
Supports [blood-brain barrier](/entities/blood-brain-barrier) function
Disease Associations
Liver Disease
GAT2 expression is altered in liver disease, affecting GABA metabolism and contributing to hepatic encephalopathy. Elevated GABA in hepatic failure is partly due to modified transporter function. The portosystemic shunting in cirrhosis leads to increased GABA tone. [@kristensen2011]
Kidney Disease
Renal GAT2 may be affected in various nephropathies. GABA transporters in the kidney contribute to tubular handling of metabolites. [@zhou2004]
Epilepsy
While less studied than GAT1, GAT2 may have compensatory roles in epilepsy. Some anticonvulsants affect multiple GABA transporter subtypes. The relative contributions of GAT1, GAT2, and GAT3 vary by brain region. [@dalby2003]
Neurodegeneration
Altered GAT2 expression has been reported in: [@wu2011]
[Alzheimer's disease](/diseases/alzheimers-disease): Modified in [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex)
[Parkinson's disease](/diseases/parkinsons-disease): Altered in basal ganglia
Huntington's disease: Dysregulated in striatum
The functional significance remains under investigation. [@gupta2016]
Therapeutic Potential
GAT2 is a less-explored drug target compared to GAT1. However: [@madsen2009]
GAT2-selective inhibitors could target peripheral GABA without CNS effects
GAT2 modulators may benefit liver disease
Understanding GAT2 function informs GABA transporter biology
[Borden et al., Molecular cloning reveals a novel rat brain GABA transporter (1992) (1992)](https://pubmed.ncbi.nlm.nih.gov/1330526/)
[Guastella et al., Cloning and expression of a GABA transporter (1992) (1992)](https://pubmed.ncbi.nlm.nih.gov/1330527/)
[Borden et al., GABA transporter subtypes: pharmacological heterogeneity and division into subtypes (1994) (1994)](https://pubmed.ncbi.nlm.nih.gov/7964268/)
[Kanner et al., Sodium-coupled GABA uptake (1983) (1983)](https://pubmed.ncbi.nlm.nih.gov/6134101/)
[Minelli et al., GAT-1 and GAT-2 expression in the rat brain (1996) (1996)](https://pubmed.ncbi.nlm.nih.gov/8627352/)
[Conti et al., GABA transporters in the mammalian brain (1999) (1999)](https://pubmed.ncbi.nlm.nih.gov/10542326/)
[Decavel et al., Distribution of GABA transporters (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9021717/)
[Richerson et al., GABA transporters as targets for anticonvulsant drugs (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11445310/)
[Schousboe et al., GABA transporters: pharmacological targets (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/14528228/)
[Kristensen et al., SLC6A neurotransmitter transporters (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21900461/)
[Zhou et al., GABA transporters in astrocytes (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15050911/)
[Dalby et al., GABA transporter inhibition (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/12871642/)
[Wu et al., GAT2 expression in liver disease (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21381068/)
[Gupta et al., GABA transporters in hepatic encephalopathy (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/26916528/)
[Madsen et al., GABA transporter distribution in brain (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19153658/)