A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels.

Yangyu Wu,Zhuyuan Chen,Cecilia M Canessa

doi:10.7554/elife.45851

Abstract

ASICs are proton-gated sodium channels expressed in neurons. Structures of chicken ASIC1 in three conformations have advanced understanding of proton-mediated gating; however, a molecular mechanism describing desensitization from open and pre-open states (steady-state desensitization or SSD) remains elusive. A distinct feature of the desensitized state is an 180o rotation of residues L415 and N416 in the β11- β12 linker that was proposed to mediate desensitization; whether and how it translates into desensitization has not been explored yet. Using electrophysiological measurements of injected Xenopus oocytes, we show that Q276 in β9 strand works with L415 and N416 to mediate both types of desensitization in ASIC1a, ASIC2a and ASIC3. Q276 functions as a valve that enables or restricts rotation of L415 and N416 to keep the linker compressed, its relaxation lengthens openings and leads to sustained currents. At low proton concentrations, the proposed mechanism working in only one of three subunits of the channel is sufficient to induce SSD.

Highlights

ASICs are sodium channels gated by external protons expressed in neurons
Q276 is a key residue involved in desensitization of human ASIC1a
Q276 is located midway b9 strand in the palm of hASIC1a with the side chain facing the interior of the central vestibule (Jasti et al, 2007); it is conserved in the four mammalian ASIC isoforms and in other vertebrate species sequenced to date (Figure 1A)

Summary

Introduction

ASICs are sodium channels gated by external protons expressed in neurons. In the peripheral nervous system activation of ASICs induces pain (Yu et al, 2010) while in the central nervous system modulates synaptic plasticity influencing the generation of memories (Wemmie et al, 2002; Yu et al, 2018), fear conditioning (Coryell et al, 2007; Wemmie et al, 2003) and extinction (Wang et al, 2018). Pathological activation of ASICs contributes to neuronal damage induced by ischemia (Duan et al, 2011; Xiong et al, 2004) and inflammatory processes (Friese et al, 2007). A characteristic of human ASICs is that protons act as agonists and as strong inhibitors by inducing two types of desensitization: low-pH desensitization shuts channels from the open state, and steady-state desensitization (SSD) shuts channels from pre-open closed states (Waldmann et al, 1997). Desensitization shapes the time course of currents in distinct ways in each of the three functional ASIC isoforms and is important to limit depolarization of neurons under global states of acidosis or local ischemia. A distinct feature of the low-pH desensitized channel is a swap of side chain orientation of L414 and N415 located in the b11-b12 linker (Baconguis and Gouaux, 2012) that led Gouaux et al to hypothesize that the linker uncouples the upper ECD from the lower channel – it works as a

Methods

Results

Conclusion