Gammaaminobutyric Acid Receptor Life Cycle

Gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter that acts at synapses through binding to ligand-gated ion channels, the GABA receptors. Clustering of the GABA-A receptor chloride channel alters receptor pharmacology on the cell surface and reduced clustering of the GABA receptor is associated with anxiety. GABA-A interacts with several proteins that modulate its clustering, endocytosis, and recycling or degradation. Plic-1 is a ubiquitin-like protein that binds to GABA-A receptors and causes them to accumulate at inhibitory synapses. Gephyrin interacts with the cytoplasmic domain of GABA-A, and with microtubules, bringing receptors together in plasma microdomains. Curiously, Gephyrin appears to be a bifunctional protein, with a domain involved in molybdenum metabolism. Another protein interacting with the GABA-A receptor is GABARAP, a microtubule-associated protein. Anchoring of the GABA-A receptor to GABARAP helps to cluster the receptor at the synaptic termini and to mediate fast synaptic transmission. GABARAP may mediate interaction of gephyrin with the GABA-A receptor and gephyrin may stabilize clusters by forming multimeric structures. GABARAP and gephyrin may play more of a role in receptor sorting and transport to the cell surface than in anchoring to the cytoplasm, since at inhibitory synapses GABARAP appears to associated with transport vesicles rather than the cell surface. The association of GABARAP with NSF (N-ethyl maleimide sensitive factor), a protein involved in intracellular vesicle transport, supports this hypothesis.

Contributor: Kosi Gramatikoff, PhD

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