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GABAA receptor membrane insertion rates are specified by their subunit composition.

ABSTRACT: ? Amino-butyric acid type-A receptors (GABARs) containing ?2 or ? subunits form separate pools of receptors in vivo, with distinct localization and function. We determined the rate of surface membrane insertion of native and recombinant ?2 and ? subunit-containing GABARs (?2-GABARs and ?-GABARs). Insertion of the ?-bungarotoxin binding site (BBS) tagged ?2 subunit (t-?2)-containing GABARs in the surface membrane of HEK293 cells occurred within minutes and reached a peak by 30 min. In contrast, insertion of the BBS-tagged ? subunit (t-?)-containing receptors required longer incubation and peaked in 120 min. Insertion of the t-?2 subunit-containing receptors was not influenced by assembling ?1 or ?4 subunits. In contrast, insertion of the ?4?3t-? subunit-containing receptors was faster than those containing ?1?3t-? subunits. The rate of insertion of native GABARs in the surface membrane of cultured hippocampal neurons, determined by an antibody saturation assay, was similar to that of the recombinant receptors expressed in HEK293 cells. Insertion of the ?2-GABARs was rapid and new ?2-GABARs were detected on the surface membrane of cell soma and dendrites within minutes. In contrast, insertion of the ?-GABARs was slow and newly inserted receptors were initially present only in the surface membrane of cell soma and later also appeared over the dendrites. Thus the rate of insertion of GABARs was dependent on their subunit composition.

SUBMITTER: Joshi S

PROVIDER: S-EPMC3791162 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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GABAA receptor membrane insertion rates are specified by their subunit composition.

Joshi Suchitra S Keith Kendra J KJ Ilyas Adeel A Kapur Jaideep J

Molecular and cellular neurosciences 20130525

γ Amino-butyric acid type-A receptors (GABARs) containing γ2 or δ subunits form separate pools of receptors in vivo, with distinct localization and function. We determined the rate of surface membrane insertion of native and recombinant γ2 and δ subunit-containing GABARs (γ2-GABARs and δ-GABARs). Insertion of the α-bungarotoxin binding site (BBS) tagged γ2 subunit (t-γ2)-containing GABARs in the surface membrane of HEK293 cells occurred within minutes and reached a peak by 30 min. In contrast, i ...[more]

PMID: 23714576

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Project description:Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABA(A,fast) and GABA(A,slow). In hippocampal area CA1, GABA(A,fast) is generally believed to underlie gamma oscillations, whereas the contribution of GABA(A,slow) to hippocampal rhythms has been speculative. Hypothesizing that GABA(A) receptors containing the beta(3) subunit contribute to GABA(A,slow) inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABA(A) receptor beta(3) subunit-deficient (beta(3)(-/-)) mice, spontaneous GABA(A,slow) inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABA(A,slow) currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing beta(3) subunits contribute substantially to GABA(A,slow) currents in pyramidal neurons. By contrast, slow inhibitory control of GABA(A,fast)-producing interneurons was unaffected in beta(3)(-/-) mice. In vivo hippocampal network activity was markedly different in the two genotypes. In beta(3)(-/-) mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency ("nesting") was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of beta(3) subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABA(A,fast) -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

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GABAA receptor membrane insertion rates are specified by their subunit composition.

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GABAA receptor membrane insertion rates are specified by their subunit composition.

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