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1 Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
* To whom correspondence should be addressed. E-mail: Stephan.Kellenberger{at}ipharm.unil.ch.
Extracellular acidification has been shown to generate action potentials in several types of neurons. In this study we have investigated the implication of acid-sensing ion channels (ASICs) in acid-induced action potential generation in brain neurons. ASICs are neuronal Na+ channels that belong to the ENaC/degenerin family and are transiently activated by a rapid drop in extracellular pH. We compared in cultured hippocampal neurons pharmacological and biophysical properties of acid-induced action potential generation with these properties of ASIC currents. This showed that acid-induced action potential generation in these neurons is essentially due to ASIC activation. We demonstrate for the first time that the probability of inducing action potentials correlates with the current entry through ASICs. We also show that ASIC activation in combination with other excitatory stimuli can either facilitate action potential generation or inhibit action potential bursts, depending on the conditions. ASIC-mediated generation and modulation of action potentials can be induced by extracellular pH changes from 7.4 to pH values slightly below pH 7. Such local extracellular pH values may be reached by the pH fluctuations due to normal neuronal activity. Furthermore, in the plasma membrane ASICs are localized in close proximity to voltage-gated Na+ and K+ channels, providing the conditions necessary for the transduction of local pH changes into electrical signals.
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