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.
Bibliographical noteFunding Information:
We thank Chris Bond for help in preparing molecular constructs, Lori Vaskalis for help in preparing figures, Michel Lazdunski for ASIC clones, Mark Voigt for P2X clones, and Gary Banker for providing constructs for fluorescent proteins. L.A.N. received a scholarship from CAPES-Brasil. L.F. discovered ATP sensitization of ASICs on sensory neurons and did most of the experiments with neurons. W.T.B., L.A.N., and V.S. did the electrophysiology experiments with transfected cell lines. F.G.W. did the immunocytochemistry in the Elde laboratory. M.K. and W.T.B. did FRET experiments in the Almers laboratory. J.M.-H. made molecular constructs and prepared plasmids in the Adelman laboratory. L.F., W.T.B., and E.W.M. designed experiments and wrote the manuscript. The work was supported by the NIH (NS37010 and HL64840) and the American Heart Association (0750053Z).