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The Journal of Neuroscience, November 28, 2007, 27(48):13251-13260; doi:10.1523/JNEUROSCI.2135-07.2007

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Cellular/Molecular
Modulation of Acid-Sensing Ion Channel Activity by Nitric Oxide

Hervé Cadiou,¹ Milena Studer,¹ Nicholas G. Jones,² Ewan St. J. Smith,¹ Angela Ballard,² Stephen B. McMahon,² and Peter A. McNaughton¹

¹Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom, and ²Neurorestoration Group, Wolfson Centre for Age Related Diseases, King's College London, London SE1 1UL, United Kingdom

Correspondence should be addressed to Peter A. McNaughton, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. Email: pam42{at}cam.ac.uk

Acid-sensing ion channels (ASICs) are a class of ion channels activated by extracellular protons and are believed to mediate the pain caused by tissue acidosis. Although ASICs have been widely studied, little is known about their regulation by inflammatory mediators. Here, we provide evidence that nitric oxide (NO) potentiates the activity of ASICs. Whole-cell patch-clamp recordings were performed on neonatal rat cultured dorsal root ganglion neurons and on ASIC isoforms expressed in CHO cells. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) potentiates proton-gated currents in DRG neurons and proton-gated currents in CHO cells expressing each of the acid-sensitive ASIC subunits. Modulators of the cGMP/PKG pathway had no effect on the potentiation, but in excised patches from CHO cells expressing ASIC2a, the potentiation could be reversed by externally applied reducing agents. NO therefore has a direct external effect on the ASIC ion channel, probably through oxidization of cysteine residues. Complementary psychophysiological studies were performed using iontophoresis of acidic solutions through the skin of human volunteers. Topical application of the NO donor glyceryl trinitrate significantly increased acid-evoked pain but did not affect heat or mechanical pain thresholds. ASICs may therefore play an important role in the pain associated with metabolic stress and inflammation, where both tissue acidosis and a high level of NO are present.

Key words: pain; inflammation; ASIC; proton-gated currents; nitric oxide; acid

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Received May 9, 2007; revised Oct. 17, 2007; accepted Oct. 17, 2007.

Correspondence should be addressed to Peter A. McNaughton, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. Email: pam42{at}cam.ac.uk

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