GABA transporters (gamma-aminobutyric acidtransporters) are a family of neurotransmitter / sodiumsymporters, belonging to thesolute carrier 6 (SLC6) family.[1][2] They are found in various regions of thebrain in different cell types, such asneurons andastrocytes.
These transporters are primarily responsible for the regulation of extracellular GABA concentration during basal and synaptic activity. They are responsible for creating a GABA gradient which is determined by themembrane potential, and the concentration of Na+ and Cl−. They are also present on theplasma membrane of neurons andglia which help define their function of regulation of GABA concentration as they act as the receptors that facilitate recycling of GABA in the extracellular space.[1] GABA transporters are a common target foranticonvulsant drugs against seizure disorders such asepilepsy.[3]
The GABA transporter group consists of six different transporters:
GAT1 and GAT3 are the major GABA transporters in the brain andspinal cord, expressed by both neurons and some astrocytes.[4] GAT2 and BGT1 are also expressed in the brain, but at low levels and mostly in themeninges. GAT2 also transportstaurine, while BGT1 transportsbetaine. These two transporters are predominantly expressed in theliver, but are also found in thekidneys and, as mentioned above, in the meninges.[4]
GABA transporters in the plasma membrane help in regulating the concentration of GABA in theextracellular matrix by reabsorbing the transmitter and clearing thesynapse. They transiently bind to GABA in the extracellular matrix and translocate the transmitter in thecytoplasm. The GABA transmitters are not broken down but are cleared via GABA transporters through re-absorption from thesynaptic cleft.[1] There is only a 20% loss of the transmitters during each re-absorption while nearly 80% is recycled.[2] The plasma membrane GABA transporters maintain an extracellular GABA concentration in the vicinity of the synapse to control the activity of theGABA receptors. The GABAergic synaptic transmission controls the generation of membrane potential rhythmic changes as the transporters are dependent on Na+ and Cl− ions moving in and out of the across the membrane which are determinants of membrane potential. These changes rely on the precise timing of GABA receptors activation which in turn are dependent upon the release and clearance of GABA in theextracellular space. This reuptake of neurotransmitters plays a significant role in the overall process of synaptic transmission. The GABA transporter is an active system,electrogenic, a voltage-dependent which relies on the inwardelectrochemical gradient of Na+ ions instead of ATP.[5] It also has low micromolecular affinity to GABA with aMichaelis-Menten constant of 2.5 μM,[1] and requires the presence of Cl- ions in the extracellular matrix. The GABA transporter help creates anequilibrium of GABA and will work in the reverse direction if needed to maintain the baseline concentration of GABA in the system.[1]
The structure of Sl6 family transporters share 20-25% sequence similarity with LeuTA[6] providing an evolutionary relationship between the transporter and the leucine transporter protein.[2] Because of the similarity, the LeuTa protein provides a very close template model for the studying the transporters in greater detail.[1] The GABA transporter exists in two different conformations. The transporters have general structure of 12 alpha helices with both end - N Terminus and C-terminus in the cytoplasm withglycosylation sequence in the transmembrane helices.[7] They also exhibitligand gated ion channel properties as well as substrate dependent properties of leak current. The amino acid sequence ranges from 599 (GAT1) to 700 for glycine transporters.[5]
GABA creates an inhibitory tone in thecerebral cortex to counterbalance the neuronal excitability.[3] An imbalance between the excitability and inhibition often lead toseizures. To help with epilepsy disorder,anticonvulsant drugs are designed which specifically attack the GABA system. These drugs often attack the transporters blocking their activity, which affects the neuronal excitability. Anticonvulsants such asTiagabine attack the GABA transporters inhibiting the uptake of GABA neurotransmitter. In patients withtemporal lobe seizures, there is a decrease in GABA release because of the impairment of transporters. Drugs such asVigabatrin cause reversals in GABA transporters that increase the concentration of GABA in the synapse which helps in inhibiting the neuronal excitability.[3]
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