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

Neuron. 2010 Nov 18;68(4):739-49. doi: 10.1016/j.neuron.2010.09.029.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channels
  • Acidosis, Lactic / metabolism
  • Acidosis, Lactic / physiopathology
  • Adenosine Triphosphate / metabolism*
  • Adenosine Triphosphate / physiology
  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • COS Cells
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Ischemia / metabolism*
  • Ischemia / physiopathology
  • Molecular Sequence Data
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / innervation*
  • Muscle, Skeletal / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X5 / metabolism*
  • Receptors, Purinergic P2X5 / physiology
  • Sensory Receptor Cells / metabolism*
  • Sensory Receptor Cells / pathology
  • Sensory Receptor Cells / physiology
  • Sodium Channels / metabolism*
  • Sodium Channels / physiology


  • ASIC3 protein, human
  • Acid Sensing Ion Channels
  • Receptors, Purinergic P2X5
  • Sodium Channels
  • Adenosine Triphosphate