Assembly, trafficking and function of 122 GABA(A) receptors are regulated by N-terminal regions, in a subunit-specific manner

作者：Wong Lik Wei; Tae Han Shen; Cromer Brett A^*

来源：Journal of Neurochemistry, 2015, 134(5): 819-832.

DOI：10.1111/jnc.13175

• GABAA receptor
• ligand-gated ion channels
• receptor assembly
• trafficking

GABA(A) receptors are pentameric ligand-gated ion channels that mediate inhibitory fast synaptic transmission in the central nervous system. Consistent with recent pentameric ligand-gated ion channels structures, sequence analysis predicts an -helix near the N-terminus of each GABA(A) receptor subunit. Preceding each -helix are 8-36 additional residues, which we term the N-terminal extension. In homomeric GABA(C) receptors and nicotinic acetylcholine receptors, the N-terminal -helix is functionally essential. Here, we determined the role of the N-terminal extension and putative -helix in heteromeric 122 GABA(A) receptors. This role was most prominent in the 1 subunit, with deletion of the N-terminal extension or further deletion of the putative -helix both dramatically reduced the number of functional receptors at the cell surface. Conversely, deletion of the 2 or 2N-terminal extension had little effect on the number of functional cell surface receptors. Additional deletion of the putative -helix in the 2 or 2 subunits did, however, decrease both functional cell surface receptors and incorporation of the 2 subunit into mature receptors. In the 2 subunit only, -helix deletions affected GABA sensitivity and desensitization. Our findings demonstrate that N-terminal extensions and -helices make key subunit-specific contributions to assembly, consistent with both regions being involved in inter-subunit interactions.

• 出版日期2015-9