Signaling Pathways in Proton and Non-proton ASIC1a Activation

Abstract

Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases as well as pain conditions. Classically, ASICs are described as transiently activated by a reduced pH, followed by desensitization; the activation allows sodium influx, and in the case of ASIC1a-composed channels, also calcium to some degree. Several factors are emerging and extensively analyzed as modulators, activating, inhibiting, and potentiating specific channel subunits. However, the signaling pathways triggered by channel activation are only starting to be revealed.The channel has been recently shown to be activated through a mechanism other than proton-mediated. Indeed, the large extracellular loop of these channels opens the possibility that other non-proton ligands might exist. One such molecule discovered was a toxin present in the Texas coral snake venom. The finding was associated with the activation of the channel at neutral pH via the toxin and causing intense and unremitting pain.By using different pharmacological tools, we analyzed the downstream signaling pathway triggered either by the proton and non-proton activation for human, mouse, and rat ASIC1a-composed channels in in vitro models. We show that for all species analyzed, the non-protonic mode of activation determines the activation of the ERK signaling cascade at a higher level and duration compared to the proton mode.This study adds to the growing evidence of the important role ASIC1a channels play in different physiological and pathological conditions and also hints at a possible pathological mechanism for a sustained effect.

Dynamic Distribution of ASIC1a Channels and Other Proteins within Cells Detected through Fractionation

“…This Nu fraction was heavily phosphorylated, as has been documented before and shown in Supplementary Figure S1C. The importance of ERK in signaling cascades has been widely studied as a master switch [25] and player involved in the downstream signaling of ASIC1a activation [26]. This work provides additional tools to further characterize these mechanisms.…”

Segmental Upregulation of ASIC1 Channels in the Formalin Acute Pain Mouse Model

“…Okine et al documented the activation of ERK at the ACC in the formalin rat model connected to the G-protein coupled receptor, GPR5, with endogenous activation of GPR55 signaling and increased ERK phosphorylation in the ACC facilitating inflammatory pain via top-down modulation of descending pain control [26]. The phosphorylation of the ERK kinase has also been linked to the activation of ASIC1 channels [19,30]. We showed that ASIC1 channels contribute to the ERK signaling pathway in this pain model (Figure 3B and Figure S1) which further links the channel to the pain pathway.…”

“…We previously documented the contribution of ASIC1a channels to the activation of the ERK pathway [18,19]. This pathway is recognized as one involved in pain [20][21][22][23][24][25].…”

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

“…This stabilization of the open state can be shown on the potentiation of the ASIC2a current by MitTx, involving a drastic shifting of its pH-dependent activation curve towards less acidic pH (pH 0.5 shifted from 3.5 to 6.0) [ 99 ]. The overlap of the binding between MitTx-β and PcTx1 on the thumb domain explains why the binding and biological activity of MitTx and PcTx1 are mutually exclusive [ 99 , 140 ].…”