GABA-A receptor life cycle
Gamma-aminobutyric acid (GABA) receptors (GABA-A receptors)
are ligand-gated ion channels that mediate fast synaptic inhibition in
brain and spinal cord. These receptors are heteropentamers that can be
assembled from seven subunit classes .
Most native GABA-A receptor subtypes consist of two alpha, two
beta and one gamma subunits, e.g. GABA-A receptor
GABA-A receptors are synthesized and assembled in the Endoplasmic
Reticulum (EPR). Then, GABA-A receptors undergo maturation in the
Golgi and are transported to the plasma membrane through the secretory
Within EPR, the ubiquitin-like protein Ubiquilin-1 directly
interacts with GABA-A receptor alpha and beta subunits (e.g., GABA-A
receptor alpha-1 subunit and GABA-A receptor beta-2 subunit)
and increases their stability. As a result, Ubiquilin-1
facilitates the insertion of GABA-A receptor into the neuronal
cell surface , .
Likewise, the GABA(A) receptor-associated protein (GABARAP) binds
directly to GABA-A receptor gamma-2 subunit regulating the
delivery of the gamma-2-containing GABA-A receptors to the cell surface
membrane. GABARAP interacts with GABA-A receptors in the
EPR and Golgi structures, and, to a lesser extent, in the secretory
vesicles, participating in the intracellular transport of the receptors ,
In the Golgi apparatus, GABARAP binds directly to
N-ethylmaleimide-sensitive factor (NSF), a critical regulator of
vesicular dependent protein trafficking .
NSF is a chaperone that activates SNARE proteins in membrane
fusion events .
NSF plays an important role in regulating GABA-A receptor
cell surface expression. NSF can be targeted to GABA-A receptor
via 2 distinct mechanisms: indirectly, via interaction with GABARAP,
which specifically binds to theGABA-A receptor gamma-2 subunit,
and directly, via interaction with the receptor beta subunits (e.g., GABA-A
receptor beta-2 subunit). Interaction of GABA-A receptor with GABARAP/
NSF complex can regulate the trafficking of GABA-A receptor
from the Golgi to the cell surface. Direct interaction of GABA-A
receptor gamma-2 subunit with NSF can regulate GABA-A
receptor insertion at the plasma membrane .
Phospholipase C-like 1 (PLCL1) and Phospholipase C-like 2 (PLCL2)
bind to GABARAP and regulate its association with GABA-A
receptors in the Golgi. The formation of complexes among GABA-A
receptor beta subunits (e.g., GABA-A receptor beta-2 subunit), GABARAP,
and PLCL1 / PLCL2 can facilitate the association of GABARAP
with the GABA-A receptor gamma-2 subunit, and thus increase the
cell surface expression of the GABA-A receptor; however, the
precise molecular mechanisms remain to be elucidated .
Synaptic GABA-A receptors reach their destination through the
lateral movement in the plasma membrane, where they mediate inhibitory
Gephyrin is a Tubulin-binding protein concentrated in the
postsynaptic membrane at many inhibitory synapses. Gephyrin is
needed for clustering GABA-A receptors that contain theGABA-A
receptor gamma-2 subunit. GABARAP can promote the recruitment
of Gephyrin to the plasma membrane and organize postsynaptic GABA-A
receptors by linking them to Gephyrin .
Endocytosis regulates the cell surface expression of GABA-A receptors.
This is one of the mechanisms of the modulation of GABAergic
transmission. Synaptic GABA-A receptors undergo constitutive Dynamin-dependent,
Clathrin-mediated endocytosis underlying receptor recycling or
degradation processes. Endocytosis process is facilitated by the adaptor
protein 2 complex (AP complex 2) .
The unphosphorylated forms of GABA-A receptor beta subunits
(e.g., GABA-A receptor beta-2 subunit) associate with the AP
complex 2 musubunit (AP complex 2 medium (mu) chain),
therefore GABA-A receptors are constitutively endocytosed. PLCL1
enhances the de-phosphorylation of GABA-A receptor beta subunits by
acting as a scaffold protein of the protein phosphatases (e.g., PP1-cat)
and regulates the phospho-dependent Clathrin/ AP complex 2 -mediated
receptor endocytosis .
From the endosomal system GABA-A receptors are either recycled to
the cell surface or degraded in the lysosomes. Another degradation
system works through the proteasome after ubiquitination ,
regulation of GABA(A) receptors at synaptic sites. Brain research.
Brain research reviews 2002 Jun;39(1):74-83
Coyle JE, Nikolov DB
lessons for synaptogenesis. The Neuroscientist : a review journal
bringing neurobiology, neurology and psychiatry 2003 Jun;9(3):205-16
Bedford FK, Kittler JT, Muller E, Thomas P, Uren JM, Merlo D, Wisden
W, Triller A, Smart TG, Moss SJ
receptor cell surface number and subunit stability are regulated by
the ubiquitin-like protein Plic-1. Nature neuroscience 2001
Saliba RS, Pangalos M, Moss SJ
ubiquitin-like protein Plic-1 enhances the membrane insertion of GABAA
receptors by increasing their stability within the endoplasmic
reticulum. The Journal of biological chemistry 2008 Jul
Chen ZW, Olsen RW
receptor associated proteins: a key factor regulating GABAA receptor
function. Journal of neurochemistry 2007 Jan;100(2):279-94
Kittler JT, Rostaing P, Schiavo G, Fritschy JM, Olsen R, Triller A,
subcellular distribution of GABARAP and its ability to interact with
NSF suggest a role for this protein in the intracellular transport of
GABA(A) receptors. Molecular and cellular neurosciences 2001
Goto H, Terunuma M, Kanematsu T, Misumi Y, Moss SJ, Hirata M
interaction of N-ethylmaleimide-sensitive factor with GABA(A) receptor
beta subunits. Molecular and cellular neurosciences 2005
Kanematsu T, Mizokami A, Watanabe K, Hirata M
of GABA(A)-receptor surface expression with special reference to the
involvement of GABARAP (GABA(A) receptor-associated protein) and PRIP
(phospholipase C-related, but catalytically inactive protein).
Journal of pharmacological sciences 2007 Aug;104(4):285-92
Kittler JT, Chen G, Honing S, Bogdanov Y, McAinsh K, Arancibia-Carcamo
IL, Jovanovic JN, Pangalos MN, Haucke V, Yan Z, Moss SJ
binding of the clathrin AP2 adaptor complex to GABAA receptors
regulates the efficacy of inhibitory synaptic transmission.
Proceedings of the National Academy of Sciences of the United States
of America 2005 Oct 11;102(41):14871-6
Barnes EM Jr
trafficking of GABA(A) receptors. Life sciences 2000 Feb