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Role of the ρ1 GABA(C) receptor N-terminus in assembly, trafficking and function



Role of the ρ1 GABA(C) receptor N-terminus in assembly, trafficking and function



Acs Chemical Neuroscience 5(12): 1266-1277



The GABAC receptor and closely related GABAA receptor are members of the pentameric ligand-gated ion channels (pLGICs) superfamily and mediate inhibitory fast synaptic transmission in the nervous system. Each pLGIC subunit comprises an N-terminal extracellular agonist-binding domain followed by a channel domain and a variable intracellular domain. Available structural information shows that the core of the agonist-binding domain is a β sandwich of ten β-strands, which form the agonist-binding pocket at the subunit interface. This β-sandwich is preceded by an N-terminal α-helix in eukaryotic structures but not in prokaryotic structures. The N-terminal α-helix has been shown to be functionally essential in α7 nicotinic acetylcholine receptors. Sequence analysis of GABAC and GABAA receptors predicts an α-helix in a similar position but preceded by 8 to 46 additional residues, of unknown function, which we term the N-terminal extension. To test the functional role of both the N-terminal extension and the putative N-terminal α-helix in the ρ1 GABAC receptor, we created a series of deletions from the N-terminus. The N-terminal extension was not functionally essential, but its removal did reduce both cell surface expression and cooperativity of agonist-gated channel function. Further deletion of the putative N-terminal α-helix abolished receptor function by preventing cell-surface expression. Our results further demonstrate the essential role of the N-terminal α-helix in the assembly and trafficking of eukaryotic pLGICs. They also provide evidence that the N-terminal extension, although not essential, contributes to receptor assembly, trafficking and conformational changes associated with ligand gating.

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Accession: 055614766

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PMID: 25347026

DOI: 10.1021/cn500220t


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