Recruitment of Plasma Membrane GABA-A Receptors by Submembranous Gephyrin/Collybistin Clusters
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It has been shown that subunit composition is the main determinant of the synaptic or extrasynaptic localization of GABA A receptors (GABA A Rs). Synaptic and extrasynaptic GABA A Rs are involved in phasic and tonic inhibition, respectively. It has been proposed that synaptic GABA A Rs bind to the postsynaptic gephyrin/collybistin (Geph/CB) lattice, but not the typically extrasynaptic GABA A Rs. Nevertheless, there are no studies of the direct binding of various types of GABA A Rs with the submembranous Geph/CB lattice in the absence of other synaptic proteins, some of which are known to interact with GABA A Rs. We have reconstituted GABA A Rs of various subunit compositions, together with the Geph/CB scaffold, in HEK293 cells, and have investigated the recruitment of surface GABA A Rs by submembranous Geph/CB clusters. Results show that the typically synaptic α1β3γ2 GABA A Rs were trapped by submembranous Geph/CB clusters. The α5β3γ2 GABA A Rs, which are both synaptic and extrasynaptic, were also trapped by Geph/CB clusters. Extrasynaptic α4β3δ GABA A Rs consistently showed little or no trapping by the Geph/CB clusters. However, the extrasynaptic α6β3δ, α1β3, α6β3 (and less α4β3) GABA A Rs were highly trapped by the Geph/CB clusters. AMPA and NMDA glutamate receptors were not trapped. The results suggest: (I) in the absence of other synaptic molecules, the Geph/CB lattice has the capacity to trap not only synaptic but also several typically extrasynaptic GABA A Rs; (II) the…
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Experimental reconstitution studies in HEK293 cells have demonstrated that the gephyrin/CB lattice can directly trap various GABAAR subunit compositions, including typically synaptic α1β3γ2 GABAARs and some extrasynaptic subtypes like α6β3δ and α1β3.
“Experimental reconstitution studies in HEK293 cells have demonstrated that the gephyrin/CB lattice can directly trap various GABAAR subunit compositions, including typically synaptic α1β3γ2 GABAARs and some extrasynaptic subtypes like α6β3δ and α1β3.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Gephyrin is essential for the clustering and anchoring of a large proportion of synaptic GABAARs, though not all.
“Gephyrin is essential for the clustering and anchoring of a large proportion of synaptic GABAARs, though not all.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
GABAARs are initially delivered to the cell surface at non-synaptic sites via exocytosis and then undergo lateral diffusion in the plasma membrane to be trapped at the synapse.
“GABAARs are initially delivered to the cell surface at non-synaptic sites via exocytosis and then undergo lateral diffusion in the plasma membrane to be trapped at the synapse.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Other extrasynaptic receptors, such as α4β3δ, show little or no trapping, suggesting that additional neuronal mechanisms prevent the trapping of certain extrasynaptic GABAARs by the gephyrin/CB lattice in neurons.
“However, other extrasynaptic receptors, such as α4β3δ, show little or no trapping, suggesting that additional neuronal mechanisms are at play to prevent the trapping of certain extrasynaptic GABAARs by the gephyrin/CB lattice in neurons [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Trapping of GABAARs at the synapse is thought to occur through the interaction of the large intracellular loop of the α subunits of synaptic GABAARs with the postsynaptic Gephyrin/CB lattice.
“This trapping is thought to occur through the interaction of the large intracellular loop (IL) of the α subunits of synaptic GABAARs with the postsynaptic Gephyrin/CB lattice.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
The intracellular loop of the α2 GABAAR subunit not only binds to gephyrin but also activates collybistin, which is important for targeting α2 GABAARs to the axon initial segment.
“Notably, the IL of the α2 GABAAR subunit not only binds to gephyrin but also activates collybistin, which is important for targeting α2 GABAARs to the axon initial segment.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Gephyrin post-translational modifications modulate its affinity for GABAergic and glycinergic receptors, thus balancing inhibitory stability with plastic remodeling.
“These modulate its affinity for GABAergic and glycinergic receptors, thus balancing inhibitory stability with plastic remodeling [57,58,59,60].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Gephyrin is a multifunctional scaffold protein that forms submembranous postsynaptic planar lattices at both GABAergic and glycinergic synapses.
“Gephyrin is a multifunctional scaffold protein that forms submembranous postsynaptic planar lattices at both GABAergic and glycinergic synapses [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
The gephyrin/CB scaffold is crucial but not the sole determinant for GABAAR synaptic localization; other synaptic molecules and post-translational modifications also contribute.
“This indicates that while the gephyrin/CB scaffold is crucial, it is not the sole determinant for GABAAR synaptic localization, and other synaptic molecules (e.g., GARLH4, neuroligin 2) and post-translational modifications (e.g., phosphorylation of gephyrin and GABAAR subunit ILs) also contribute to the complex regulation of GABAAR clustering and synaptic localization [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
The β3 subunit appears to be a major determinant for the interaction of GABAARs with gephyrin/CB clusters.
“The β3 subunit appears to be a major determinant for the interaction of GABAARs with gephyrin/CB clusters [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
The intracellular loops of α1, α2, α3, or α5 subunits bind to monomeric gephyrin in vitro and to collybistin, playing a critical role in their synaptic localization.
“Studies have shown that the ILs of α1, α2, α3, or α5 subunits bind to monomeric gephyrin in vitro and to collybistin, playing a critical role in their synaptic localization [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Collybistin acts as a guanine nucleotide exchange factor for Cdc42, and its deficiency leads to disrupted postsynaptic clustering of GABAARs and gephyrin in various brain regions, including hippocampus, amygdala, and cerebellum.
“Collybistin acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Cdc42, and its deficiency leads to disrupted postsynaptic clustering of GABAARs and Gephyrin in various brain regions, including the hippocampus, amygdala, and cerebellum [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
Collybistin binds to gephyrin and membrane phosphoinositides, thereby anchoring the gephyrin/CB lattice to the postsynaptic membrane.
“The postsynaptic scaffold also includes collybistin (CB), which binds to gephyrin and membrane phosphoinositides, thereby anchoring the gephyrin/CB lattice to the postsynaptic membrane [57].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [57]
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GABA Regulates Electrical Activity and Tumor Initiation in Melanoma
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“Gephyrin is a multifunctional scaffold protein that forms submembranous postsynaptic planar lattices at both GABAergic and glycinergic synapses [57].”
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- Authors
- George, S., Chiou, T.-T., Kanamalla, K., & De Blas, A. L.
- Affiliations
- University of Connecticut (US)
- Venue
- Cellular and Molecular Neurobiology
- Published
- 2021-02-05
- Volume
- 42
- Issue
- 5
- Pages
- 1585-1604
- ISSN
- 0272-4340 (ISSN-L)
- 1573-6830
- PMC
- PMC11421751
- OpenAlex
- W3126404023
- Cited by
- 8
- References
- 147
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-02-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cellular and Molecular Neurobiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS038752)
- University of Connecticut (Research Incentive Program Grant)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- GABAA receptor, gephyrin, collybistin, extrasynaptic GABAA receptors, synaptic localization, receptor subunit composition, tonic inhibition, phasic inhibition, receptor reconstitution, HEK293 cells
- MeSH terms
- Cell Membrane, gamma-Aminobutyric Acid, Humans, Membrane Proteins, Receptors, GABA-A, Synapses, Receptors, N-Methyl-D-Aspartate, HEK293 Cells, Rho Guanine Nucleotide Exchange Factors
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