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Slowing of the time course of acidification decreases the acid-sensing ion channel 1a current amplitude and modulates action potential firing in neurons

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Alijevic Omar, Bignucolo Olivier, Hichri Echrak, Peng Zhong, Kucera Jan P., Kellenberger Stephan,
Project Understanding the roles of mechanical stretch and of sodium channel nanodomains in cardiac excitation: a multidisciplinary approach
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Original article (peer-reviewed)

Journal Frontiers in Cellular Neuroscience
Volume (Issue) 14
Page(s) 41
Title of proceedings Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2020.00041

Open Access

Type of Open Access Publisher (Gold Open Access)


Acid-sensing ion channels (ASICs) are H+-activated neuronal Na+ channels. They are involved in fear behavior, learning, neurodegeneration after ischemic stroke and in pain sensation. ASIC activation has so far been studied only with fast pH changes, although the pH changes associated with many roles of ASICs are slow. It is currently not known whether slow pH changes can open ASICs at all. Here, we investigated to which extent slow pH changes can activate ASIC1a channels and induce action potential signaling. To this end, ASIC1a current amplitudes and charge transport in transfected Chinese hamster ovary cells, and ASIC-mediated action potential signaling in cultured cortical neurons were measured in response to defined pH ramps of 1-40 s duration from pH 7.4 to pH 6.6 or 6.0. A kinetic model of the ASIC1a current was developed and integrated into the Hodgkin-Huxley action potential model. Interestingly, whereas the ASIC1a current amplitude decreased with slower pH ramps, action potential firing was higher upon intermediate than fast acidification in cortical neurons. Indeed, fast pH changes (<4 s) induced short action potential bursts, while pH changes of intermediate speed (4-10 s) induced longer bursts. Slower pH changes (>10 s) did in many experiments not generate action potentials. Computer simulations corroborated these observations. We provide here the first description of ASIC function in response to defined slow pH changes. Our study shows that ASIC1a currents, and neuronal activity induced by ASIC1a currents, strongly depend on the speed of pH changes. Importantly, with pH changes that take >10 s to complete, ASIC1a activation is inefficient. Therefore, it is likely that currently unknown modulatory mechanisms allow ASIC activity in situations such as ischemia and inflammation.