Acid Sensing Ion Channels are Uniquely Tuned to Follow High Frequency ‘Synaptic’ Stimuli

Abstract

Synaptic transmission between neurons often proceeds as bursts of very brief neurotransmitter release at high frequencies. In response to such high frequency short duration stimulation, all neurotransmitter-gated ion channels (NGICs) desensitize or shut down (Papke et al., 2011). Acid Sensing Ion Channels (ASICs) are a family of ion channels which are activated by extracellular increases in proton concentration. Recently, ASICs have attained the status of NGICs as they respond to the transient acidification at the synaptic cleft which accompanies transmission (Du et al., 2014; Kreple et al., 2014). Given that all other NGICs desensitize during high frequency stimulation, we hypothesized that ASICs would share this feature and similarly desensitize during trains of stimuli. To test this, we excised outside-out patches from ASIC transfected CHO cells or dorsal root ganglion neurons and used rapid application methods to jump ASICs from a physiological pH solution to an activating solution of pH 5.0. To reproduce the brief time course of synaptic transmission pH jumps were 1 millisecond in duration and either single events or trains at frequencies up to 50 Hz. In contrast to all other NGICs studied, ASICs showed no desensitization to these stimuli trains at up to 50 Hz. Mechanistically, this capacity arises from ASIC's combination of slow desensitization and fast deactivation kinetics as accelerating the former induced desensitization at high frequencies. We conclude that ASICs are intrinsically, and uniquely, adapted to signal at high frequencies where other NGIC's exhibit desensitization. The ability to follow high frequency signals may explain why genetic deletion of ASICs prevents long-term potentiation (LTP) induced by high frequency stimulation. Our study reveals a unique property of ASICs compared to other NGICs and opens up new avenues for investigating the role of synaptic ASICs.