Signaling Pathways in Proton and Non-proton ASIC1a Activation

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 ca...

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Bibliographic Details
Published in:Frontiers in cellular neuroscience 2021-10, Vol.15, p.735414-735414
Main Authors: Salinas Castellanos, Libia Catalina, Uchitel, Osvaldo Daniel, Weissmann, Carina
Format: Article
Language:English
Subjects:
Acidity
Antibodies
ASIC1a
Calcium channels
Cellular Neuroscience
ERK
Ion channels
Kinases
Laboratory animals
Ligands
Membranes
MitTx
Nervous system
Neurodegenerative diseases
Neuromodulation
non-proton activation
Pain
Permeability
pH effects
Phosphorylation
Proteins
proton activation
Signal transduction
Sodium channels
Venom
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Summary: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 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 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.
ISSN:1662-5102
1662-5102
DOI:10.3389/fncel.2021.735414