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Gephyrin, the enigmatic organizer at GABAergic synapses.

Tretter V, Mukherjee J, Maric HM, Schindelin H, Sieghart W, Moss SJ - Front Cell Neurosci (2012)

Bottom Line: This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition.Gephyrin has long been known to be directly associated with glycine receptor β subunits that mediate synaptic inhibition in the spinal cord.Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Center for Brain Research, Medical University Vienna Vienna, Austria.

ABSTRACT
GABA(A) receptors are clustered at synaptic sites to achieve a high density of postsynaptic receptors opposite the input axonal terminals. This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition. A key organizer for inhibitory synaptic receptors is the 93 kDa protein gephyrin that forms oligomeric superstructures beneath the synaptic area. Gephyrin has long been known to be directly associated with glycine receptor β subunits that mediate synaptic inhibition in the spinal cord. Recently, synaptic GABA(A) receptors have also been shown to directly interact with gephyrin and interaction sites have been identified and mapped within the intracellular loops of the GABA(A) receptor α1, α2, and α3 subunits. Gephyrin-binding to GABA(A) receptors seems to be at least one order of magnitude weaker than to glycine receptors (GlyRs) and most probably is regulated by phosphorylation. Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity.

No MeSH data available.


Related in: MedlinePlus

Synaptic GABAARs containing the α2 or α3 subunit are clustered by different mechanisms. Schematic representations of GABAergic post-synapses containing the GABAAR α3 subunit (A) or the GABAAR α2 subunit (B) show the postulated differential role of collybistin in synaptic cluster formation. GABAARs containing the α3 subunit directly bind to gephyrin, while GABAARs containing the α2 subunit use collybistin as an accessory factor to enhance the affinity of binding to gephyrin. Isoforms of the cell adhesion molecule neuroligin (NL–2/4) have a preference for GABAergic synapses and have been shown to activate collybistin.
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Figure 2: Synaptic GABAARs containing the α2 or α3 subunit are clustered by different mechanisms. Schematic representations of GABAergic post-synapses containing the GABAAR α3 subunit (A) or the GABAAR α2 subunit (B) show the postulated differential role of collybistin in synaptic cluster formation. GABAARs containing the α3 subunit directly bind to gephyrin, while GABAARs containing the α2 subunit use collybistin as an accessory factor to enhance the affinity of binding to gephyrin. Isoforms of the cell adhesion molecule neuroligin (NL–2/4) have a preference for GABAergic synapses and have been shown to activate collybistin.

Mentions: Interesting features include the competition of NL-2 and GABAAR α2 subunits for the collybistin SH3-domain and the competition of collybistin and GABAAR α2 for slightly shifted, yet still overlapping sites on gephyrin (Tretter et al., 2011 and Figure 3C). The binding sites of CB and GABAAR subunits α2 and α3 on gephyrin are positioned close to each other (see Figure 3). Saiepour et al. showed that the GABAAR α3 subunit directly interacts with gephyrin, while α2, gephyrin and CB form a ternary complex, where CB strengthens the otherwise weak α2-gephyrin interaction (Saiepour et al., 2010). Therefore, synapses containing GABAARs with an α3 subunit do not need collybistin as a cofactor, while collybistin is mandatory for synapses with α2-containing GABAARs (see Figures 2A,B). The theory of a selective association of CB with certain GABAAR subtypes has been rejected in the paper by Patrizi et al., yet the interaction of CB with the synaptic complexes seems to be only transient (Patrizi et al., 2011). Therefore, not all synaptic puncta are associated with CB immunoreactivity.


Gephyrin, the enigmatic organizer at GABAergic synapses.

Tretter V, Mukherjee J, Maric HM, Schindelin H, Sieghart W, Moss SJ - Front Cell Neurosci (2012)

Synaptic GABAARs containing the α2 or α3 subunit are clustered by different mechanisms. Schematic representations of GABAergic post-synapses containing the GABAAR α3 subunit (A) or the GABAAR α2 subunit (B) show the postulated differential role of collybistin in synaptic cluster formation. GABAARs containing the α3 subunit directly bind to gephyrin, while GABAARs containing the α2 subunit use collybistin as an accessory factor to enhance the affinity of binding to gephyrin. Isoforms of the cell adhesion molecule neuroligin (NL–2/4) have a preference for GABAergic synapses and have been shown to activate collybistin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351755&req=5

Figure 2: Synaptic GABAARs containing the α2 or α3 subunit are clustered by different mechanisms. Schematic representations of GABAergic post-synapses containing the GABAAR α3 subunit (A) or the GABAAR α2 subunit (B) show the postulated differential role of collybistin in synaptic cluster formation. GABAARs containing the α3 subunit directly bind to gephyrin, while GABAARs containing the α2 subunit use collybistin as an accessory factor to enhance the affinity of binding to gephyrin. Isoforms of the cell adhesion molecule neuroligin (NL–2/4) have a preference for GABAergic synapses and have been shown to activate collybistin.
Mentions: Interesting features include the competition of NL-2 and GABAAR α2 subunits for the collybistin SH3-domain and the competition of collybistin and GABAAR α2 for slightly shifted, yet still overlapping sites on gephyrin (Tretter et al., 2011 and Figure 3C). The binding sites of CB and GABAAR subunits α2 and α3 on gephyrin are positioned close to each other (see Figure 3). Saiepour et al. showed that the GABAAR α3 subunit directly interacts with gephyrin, while α2, gephyrin and CB form a ternary complex, where CB strengthens the otherwise weak α2-gephyrin interaction (Saiepour et al., 2010). Therefore, synapses containing GABAARs with an α3 subunit do not need collybistin as a cofactor, while collybistin is mandatory for synapses with α2-containing GABAARs (see Figures 2A,B). The theory of a selective association of CB with certain GABAAR subtypes has been rejected in the paper by Patrizi et al., yet the interaction of CB with the synaptic complexes seems to be only transient (Patrizi et al., 2011). Therefore, not all synaptic puncta are associated with CB immunoreactivity.

Bottom Line: This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition.Gephyrin has long been known to be directly associated with glycine receptor β subunits that mediate synaptic inhibition in the spinal cord.Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Center for Brain Research, Medical University Vienna Vienna, Austria.

ABSTRACT
GABA(A) receptors are clustered at synaptic sites to achieve a high density of postsynaptic receptors opposite the input axonal terminals. This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition. A key organizer for inhibitory synaptic receptors is the 93 kDa protein gephyrin that forms oligomeric superstructures beneath the synaptic area. Gephyrin has long been known to be directly associated with glycine receptor β subunits that mediate synaptic inhibition in the spinal cord. Recently, synaptic GABA(A) receptors have also been shown to directly interact with gephyrin and interaction sites have been identified and mapped within the intracellular loops of the GABA(A) receptor α1, α2, and α3 subunits. Gephyrin-binding to GABA(A) receptors seems to be at least one order of magnitude weaker than to glycine receptors (GlyRs) and most probably is regulated by phosphorylation. Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity.

No MeSH data available.


Related in: MedlinePlus