Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling

Abstract

Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system.

Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy

“…In the brain, ASIC1a activation causes Ca 2þ -dependent neuronal death during prolonged acidosis following ischaemia [24,27]. Together with the recently found neurotransmitter role for protons in certain brain areas, which is based on the involvement of ASICs as postsynaptic receptors sensing rapid pH transitions [28], this list, most probably incomplete, indicates the more than impressive role of ASICs in brain function, consistent with their ubiquitous presence in the brain tissue.…”

Motoneurons regulate the central pattern generator during drug-induced locomotor-like activity in the neonatal mouse

“…Recent studies have shown that both local extracellular and intracellular pH are affected by archaerhodopsin activation ( Zeng et al, 2015 ; El-Gaby et al, 2016 ; Mahn et al, 2016 ). Because these changes can potentially affect the rhythm ( Beg et al, 2008 ; Zeng et al, 2015 ; Jalalvand et al, 2016 ), we repeated the experiments in spinal cords expressing the light-activated chloride pump halorhodopsin (eNpHR; n = 12, Figure 3A ) and activated the opsin with the same green light. As described for the ChAT-Arch cords, light suppressed the ventral root firing especially in the extensor roots ( Figure 3E ), transiently reduced the frequency, and altered the phasing of the rhythm ( Figure 3C and D ).…”

The voltage-gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord injury

“…It has been previously shown that microglia e ciently phagocytose damaged tissue and remain viable, whereas, macrophages of peripheral origin are less e cient at processing debris, and their death, in situ, may contribute to the secondary damage after CNS injury [11]. Additional mechanism may also include that Hv1 as a proton releasing channel which could activate the acid-sensing ion channel to induce neurotoxicity [14,16,41], or Hv1-mediated microglia-astrocyte interaction [42]. Taken together, the differential mechanisms mediated by Hv1 in microglia versus macrophages in microglia polarization, ROS production, maintenance of phagosomes, and proton signaling might affect the course and outcome of SCI and needs to be elucidated.…”