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.
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. [1]
GAT2 shares the core structural features of SLC6A family transporters: [2]
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: [3]
GAT2 expression differs from GAT1: [4]
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. [5]
In liver and kidney, GAT2 contributes to: [6]
The liver expresses high levels of GAT2 where it participates in the GABA-shunt, linking GABA metabolism to the urea cycle and ammonia detoxification. [7]
In regions where expressed, GAT2: [8]
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. [9]
Renal GAT2 may be affected in various nephropathies. GABA transporters in the kidney contribute to tubular handling of metabolites. [10]
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. [11]
Altered GAT2 expression has been reported in: [12]
The functional significance remains under investigation. [13]
GAT2 is a less-explored drug target compared to GAT1. However: [14]
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Gupta et al. GABA transporters in hepatic encephalopathy (2016). 2016. ↩︎
Madsen et al. GABA transporter distribution in brain (2009). 2009. ↩︎