Dynamic regulation of GABA(A) receptors at synaptic sites.
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 GABA(A)Rs and the Plic1-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 clathrin-mediated endocytosis underlying receptor recycling or degradation processes. This article discusses these recent data in the field of GABA(A)R dynamics.
Kneussel
Matthias
M
Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, D-60528 Frankfurt/Main, Germany. kneussel@mpih-frankfurt.mpg.de
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D011963:Receptors, GABA-A / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C116741:GABARAP protein, human; D008869:Microtubule-Associated Proteins; D011963:Receptors, GABA-A