Inhalational anesthetics accelerate desensitization of acid-sensing ion channels

Acid-sensing ion channels (ASICs) are neuronal Na+ channels that are activated by extracellular acidification. Inhibiting ASICs is neuroprotective in mouse models of ischemic stroke. As inhalational anesthetics interact with many ion channels and as some of them have neuroprotective effects, we hypothesized that inhalational anesthetics modulate ASICs. We expressed different homo- and heteromeric ASICs heterologously in Xenopus oocytes. We co-applied with acidic pH the halogenated inhalational anesthetics sevoflurane, desflurane, and isoflurane and the noble gases xenon and argon at concentrations that are roughly equivalent to their minimal alveolar concentrations and analyzed their effect on current kinetics and amplitude. Sevoflurane, desflurane, and isoflurane as well as xenon and argon accelerated by a factor of similar to 1.5 channel desensitization of the main ASICs of the central nervous system: homomeric ASICla and heteromeric ASIC1 a/2a and ASICla/2b. Moreover, they decreased current amplitudes by similar to 25%. For example, isoflurane accelerated desensitization of homomeric ASICla from 1.0 +/- 0.4 s (mean +/- SD) to 0.6 +/- 0.2 s (n = 12; p = 0.0003) and decreased current amplitudes from 12.1 +/- 7.5 mu A to 9.3 +/- 5.6 mu A (n = 12; p = 0.0009). While inhalational anesthetics had similar effects on 7.5 A to 9.3 +/- 5.6 mu A (n = 12; p = 0.0009). While inhalational anesthetics had similar effects on homomeric ASIC3, desensitization of ASIC1b was only accelerated by halogenated anesthetics but not noble gases; desensitization of homomeric ASIC2a was not modulated. In summary, we found a significant modulation of ASICs by different inhalational anesthetics. We conclude that ASICs should be considered as relevant targets of inhalation anesthetics. 2018 Elsevier Ltd. All rights reserved.