Interaction between GABAA receptor α1 and β2 subunits at the N-terminal peripheral regions is crucial for receptor binding and gating

Abstract

Pentameric ligand gated ion channels (pLGICs) are crucial in electrochemical signaling but exact molecular mechanisms of their activation remain elusive. So far, major effort focused on the top-down molecular pathway between the ligand binding site and the channel gate. However, recent studies revealed that pLGIC activation is associated with coordinated subunit twisting in the membrane plane. This suggests a key role of intersubunit interactions but the underlying mechanisms remain largely unknown. Herein, we investigated a "peripheral" subunit interface region of GABA_A receptor where structural modeling indicated interaction between N-terminal α₁F14 and β₂F31 residues. Our experiments underscored a crucial role of this interaction in ligand binding and gating, especially preactivation and opening, showing that the intersubunit cross-talk taking place outside (above) the top-down pathway can be strongly involved in receptor activation. Thus, described here intersubunit interaction appears to operate across a particularly long distance, affecting vast portions of the macromolecule.

Keywords: GABA(A) receptors; Homology modeling; Mutagenesis; Single-channel analysis; Structure–function.