Sensing muscle ischemia: Coincident detection of acid and ATP via interplay of two ion channels

William T. Birdsong, Leonardo Fierro, Frank G. Williams, Valeria Spelta, Ligia A. Naves, Michelle Knowles, Josephine Marsh-Haffner, John P. Adelman, Wolfhard Almers, Robert P. Elde, Edwin W. McCleskey

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102 Scopus citations

Abstract

Ischemic pain-examples include the chest pain of a heart attack and the leg pain of a 30 s sprint-occurs when muscle gets too little oxygen for its metabolic need. Lactic acid cannot act alone to trigger ischemic pain because the pH change is so small. Here, we show that another compound released from ischemic muscle, adenosine tri-phosphate (ATP), works together with acid by increasing the pH sensitivity of acid-sensing ion channel number 3 (ASIC3), the molecule used by sensory neurons to detect lactic acidosis. Our data argue that ATP acts by binding to P2X receptors that form a molecular complex with ASICs; the receptor on sensory neurons appears to be P2X5, an electrically quiet ion channel. Coincident detection of acid and ATP should confer sensory selectivity for ischemia over other conditions of acidosis.

Original languageEnglish (US)
Pages (from-to)739-749
Number of pages11
JournalNeuron
Volume68
Issue number4
DOIs
StatePublished - Nov 18 2010

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    Birdsong, W. T., Fierro, L., Williams, F. G., Spelta, V., Naves, L. A., Knowles, M., Marsh-Haffner, J., Adelman, J. P., Almers, W., Elde, R. P., & McCleskey, E. W. (2010). Sensing muscle ischemia: Coincident detection of acid and ATP via interplay of two ion channels. Neuron, 68(4), 739-749. https://doi.org/10.1016/j.neuron.2010.09.029