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Journal Article

Dynamic regulation of GABA(A) receptors at synaptic sites


Kneussel,  M.
Neurochemistry Department, Max Planck Institute for Brain Research, Max Planck Society;

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Kneussel, M. (2002). Dynamic regulation of GABA(A) receptors at synaptic sites. Brain Research Reviews, 39(1), 74-83.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002E-1AC6-7
gamma-Aminobutyric acid type A receptors (GABA(A)Rs) mediate fast synaptic inhibition in brain and spinal cord. They are ligand-gated ion channels composed of numerous distinct subunit combinations. For efficient synaptic transmission, GABA(A)Rs need to be localized to and anchored at postsynaptic sites in precise apposition to presynaptic nerve terminals that release the neurotransmitter GABA. Neurons therefore require distinct mechanisms to regulate intracellular vesicular protein traffic, plasma membrane insertion, synaptic clustering and turnover of GABA(A)Rs. The GABA(A) receptor-associated protein GABARAP interacts with the gamma2 subunit of GABA(A)Rs and displays high homology to proteins involved in membrane fusion underlying Golgi transport and autophagic processes. The binding of GABARAP with NSF, microtubules and gephyrin together with its localization at intracellular membranes suggests a role in GABA(A)R targeting and/or degradation. Growth factor tyrosine kinase receptor activation is involved in the control of GABA(A)R levels at the plasma membrane. In particular insulin recruits GABA(A)Rs to the cell surface. Furthermore, the regulation of GABA(A)R surface half-life can also be the consequence of negative modulation at the proteasome level. Plic-1, a ubiquitin-like protein binds to both the proteasome and GAB(A)Rs and the Plicl-GABA(A)R interaction is important for the maintenance of GABA-activated current amplitudes. At synaptic sites, GABA(A)Rs are clustered via gephyrin-dependent and gephyrin-independent mechanisms and may subsequently become internalized via clathrinmediated endocytosis underlying receptor recycling or degradation processes. This article discusses these recent data in the field of GABA(A)R dynamics. (C) 2002 Elsevier Science B.V. All rights reserved.