GABA synthesis, release, reuptake and degradation (Homo sapiens)
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GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. GABA modulates neuronal excitability throughout the nervous system. Disruption of GABA neurotransmission leads to many neurological diseases including epilepsy and a general anxiety disorder. GABA is synthesized by two distinct enzymes GAD67 and GAD65 that differ in their cellular localization, functional properties and co-factor requirements. GABA synthesized by GAD65 is used for neurotransmission whereas GABA synthesized by GAD67 is used for processes other than neurotransmission such as synaptogenesis and protection against neuronal injury. GABA is loaded into synaptic vesicle with the help of vesicular inhibitory amino acid transporter or VGAT. GAD65 and VGAT are functionally linked at the synaptic vesicle membrane and GABA synthesized by GAD65 is preferentially loaded into the synaptic vesicle over GABA synthesized in cytoplasm by GAD67.The GABA loaded synaptic vesicles are docked at the plasma membrane with the help of the SNARE complexes and primed by interplay between various proteins including Munc18, complexin etc. Release of GABA loaded synaptic vesicle is initiated by the arrival of action potential at the presynaptic bouton and opening of N or P/Q voltage gated Ca2+ channels. Ca2+ influx results in Ca2+ binding by synaptobrevin, which is a part of the SNARE complex that also includes SNAP25 and syntaxin, leading to synaptic vesicle fusion. Release of GABA in the synaptic cleft leads to binding of GABA by the GABA receptors and post ligand binding events.
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SLC6A1 encodes a sodium- and chloride-dependent GABA transporter 1, GAT1, which is the predominant GABA transporter in brain. It is widely distributed in the brain and co-localized to GABAergic neurons (Nelson H et al, 1990). SLC6A13 encodes a sodium- and chloride-dependent GABA transporter 2, GAT2, which is localized to GABAergic neurons in the brain. It is also found in retina, liver and kidney (Christiansen B et al, 2007). SLC6A11 encodes a sodium- and chloride-dependent GABA transporter 3, GAT3. It is expressed in the brain and localizes to GABAergic neurons (Borden LA et al, 1994).