- Title
- Protein interactions involving the γ2 large cytoplasmic loop of GABAA receptors modulate conductance
- Creator
- Everitt, Andrea B.; Seymour, Victoria A. L.; Curmi, John; Laver, Derek R.; Gage, Peter W.; Tierney, M. Louise
- Relation
- FASEB Journal Vol. 23, Issue 12, p. 4361-4369
- Publisher Link
- http://dx.doi.org/10.1096/fj.09-137042
- Publisher
- Federation of American Societies for Experimental Biology
- Resource Type
- journal article
- Date
- 2009
- Description
- Native GABAA channels display a singlechannel conductance ranging between ~10 and 90 pS. Diazepam increases the conductance of some of these native channels but never those of recombinant receptors, unless they are coexpressed with GABARAP. This trafficking protein clusters recombinant receptors in the membrane, suggesting that high-conductance channels arise from receptors that are at locally high concentrations. The amphipathic (MA) helix that is present in the large cytoplasmic loop of every subunit of all ligand-gated ion channels mediates protein-protein interactions. Here we report that when applied to insideout patches, a peptide mimicking the MA helix of the γ2 subunit (γ381-403) of the GABAA receptor abrogates the potentiating effect of diazepam on both endogenous receptors and recombinant GABAA receptors coexpressed with GABARAP, by substantially reducing their conductance. The protein interaction disrupted by the peptide did not involve GABARAP, because a shorter peptide (γ386-403) known to compete with the γ2-GABARAP interaction did not affect the conductance of recombinant αβγ receptors coexpressed with GABARAP. The requirement for receptor clustering and the fact that the γ2 MA helix is able to selfassociate support a mechanism whereby adjacent GABAA receptors interact via their γ2-subunit MA helices, altering ion permeation through each channel. Alteration of ion-channel function arising from dynamic interactions between ion channels of the same family has not been reported previously and highlights a novel way in which inhibitory neurotransmission in the brain may be differentially modulated.
- Subject
- single channel conductance; diazepams; MA helix; competitor peptides
- Identifier
- http://hdl.handle.net/1959.13/807478
- Identifier
- uon:7417
- Identifier
- ISSN:0892-6638
- Language
- eng
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