γ-aminobutyric acid type A (GABA A) receptor α subunits play a direct role in synaptic Versus extrasynaptic targeting

Xia Wu, Zheng Wu, Gang Ning, Yao Guo, Rashid Ali, Robert L. Macdonald, Angel L. De Blas, Bernhard Luscher, Gong Chen

Research output: Contribution to journalArticle

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Abstract

GABA A receptors (GABA A-Rs) are localized at both synaptic and extrasynaptic sites, mediating phasic and tonic inhibition, respectively. Previous studies suggest an important role of γ2 and δ subunits in synaptic versus extrasynaptic targeting of GABA A-Rs. Here, we demonstrate differential function of α2 and α6 subunits in guiding the localization of GABA A-Rs. To study the targeting of specific subtypes of GABA A-Rs, we used a molecularly engineered GABAergic synapse model to precisely control the GABA A-R subunit composition. We found that in neuron-HEK cell heterosynapses, GABAergic events mediated by α2β3γ2 receptors were very fast (rise time ∼2 ms), whereas events mediated by α6β3δ receptors were very slow (rise time ∼20 ms). Such an order of magnitude difference in rise time could not be attributed to the minute differences in receptor kinetics. Interestingly, synaptic events mediated by α6β3 or α6β3γ2 receptors were significantly slower than those mediated by α2β3 or α2β3γ2 receptors, suggesting a differential role of α subunit in receptor targeting. This was confirmed by differential targeting of the same δ-γ2 chimeric subunits to synaptic or extrasynaptic sites, depending on whether it was co-assembled with the α2 or α6 subunit. In addition, insertion of a gephyrin-binding site into the intracellular domain of α6 and δ subunits brought α6β3δ receptors closer to synaptic sites. Therefore, the α subunits, together with the γ2 and δ subunits, play a critical role in governing synaptic versus extrasynaptic targeting of GABA A-Rs, possibly through differential interactions with gephyrin.

Original languageEnglish (US)
Pages (from-to)27417-27430
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number33
DOIs
StatePublished - Aug 10 2012

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Aminobutyrates
GABA-A Receptors
gamma-Aminobutyric Acid
Synapses
Neurons
Binding Sites
Kinetics
Chemical analysis
gephyrin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "γ-aminobutyric acid type A (GABA A) receptor α subunits play a direct role in synaptic Versus extrasynaptic targeting",
abstract = "GABA A receptors (GABA A-Rs) are localized at both synaptic and extrasynaptic sites, mediating phasic and tonic inhibition, respectively. Previous studies suggest an important role of γ2 and δ subunits in synaptic versus extrasynaptic targeting of GABA A-Rs. Here, we demonstrate differential function of α2 and α6 subunits in guiding the localization of GABA A-Rs. To study the targeting of specific subtypes of GABA A-Rs, we used a molecularly engineered GABAergic synapse model to precisely control the GABA A-R subunit composition. We found that in neuron-HEK cell heterosynapses, GABAergic events mediated by α2β3γ2 receptors were very fast (rise time ∼2 ms), whereas events mediated by α6β3δ receptors were very slow (rise time ∼20 ms). Such an order of magnitude difference in rise time could not be attributed to the minute differences in receptor kinetics. Interestingly, synaptic events mediated by α6β3 or α6β3γ2 receptors were significantly slower than those mediated by α2β3 or α2β3γ2 receptors, suggesting a differential role of α subunit in receptor targeting. This was confirmed by differential targeting of the same δ-γ2 chimeric subunits to synaptic or extrasynaptic sites, depending on whether it was co-assembled with the α2 or α6 subunit. In addition, insertion of a gephyrin-binding site into the intracellular domain of α6 and δ subunits brought α6β3δ receptors closer to synaptic sites. Therefore, the α subunits, together with the γ2 and δ subunits, play a critical role in governing synaptic versus extrasynaptic targeting of GABA A-Rs, possibly through differential interactions with gephyrin.",
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γ-aminobutyric acid type A (GABA A) receptor α subunits play a direct role in synaptic Versus extrasynaptic targeting. / Wu, Xia; Wu, Zheng; Ning, Gang; Guo, Yao; Ali, Rashid; Macdonald, Robert L.; De Blas, Angel L.; Luscher, Bernhard; Chen, Gong.

In: Journal of Biological Chemistry, Vol. 287, No. 33, 10.08.2012, p. 27417-27430.

Research output: Contribution to journalArticle

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AU - Wu, Xia

AU - Wu, Zheng

AU - Ning, Gang

AU - Guo, Yao

AU - Ali, Rashid

AU - Macdonald, Robert L.

AU - De Blas, Angel L.

AU - Luscher, Bernhard

AU - Chen, Gong

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