Abstract
Acid-sensing ion channels (ASICs) are proton-gated sodium-selective channels that are expressed in the peripheral and central nervous systems. ASIC1a is one of the most intensively studied isoforms due to its importance and wide representation in organisms, but it is still largely unexplored as a target for therapy. In this study, we demonstrated response of the ASIC1a to acidification in the presence of the daurisoline (DAU) ligand. DAU alone did not activate the channel, but in combination with protons, it produced the second peak component of the ASIC1a current. This second peak differs from the sustained component (which is induced by RF-amide peptides), as the second (DAU-induced) peak is completely desensitized, with the same kinetics as the main peak. The co-application of DAU and mambalgin-2 indicated that their binding sites do not overlap. Additionally, we found an asymmetry in the pH activation curve of the channel, which was well-described by a mathematical model based on the multiplied probabilities of protons binding with a pool of high-cooperative sites and a single proton binding with a non-cooperative site. In this model, DAU targeted the pool of high-cooperative sites and, when applied with protons, acted as an inhibitor of ASIC1a activation. Moreover, DAU’s occupation of the same binding site most probably reverses the channel from steady-state desensitization in the pH 6.9–7.3 range. DAU features disclose new opportunities in studies of ASIC structure and function.
Highlights
Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelialNa+ -channel superfamily
We found an asymmetry in the pH activation curve of the channel, which was well-described by a mathematical model based on the multiplied probabilities of protons binding with a pool of high-cooperative sites and a single proton binding with a non-cooperative site
Because ASIC1 and ASIC3 contribute to hyperalgesia, the molecules that inhibit ASIC1 and ASIC3 activity have been recognized as prospective analgesic drugs [11,12,13,14,15,16]
Summary
Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelialNa+ -channel superfamily. Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelial. ASICs, especially the ASIC1a isoform, are widely expressed in the peripheral and central nervous systems, where they are involved in physiological and pathological processes such as synaptic plasticity, neuronal injury, and nociception [4,5,6]. ASIC1a activation mediates neurodegeneration and death under pathological conditions such as cerebral ischemia, inflammation, and traumatic injury [7,8,9,10]. For the central nervous system, the major impact of proton sensing is attributed to ASIC1a containing homotrimeric or heterotrimeric ion channels. This subtype differs from others in terms of biophysical properties, pH sensitivity, and ligand specificity.
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