title: Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels.
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.
authors.affiliation: Vollum Institute, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Birdsong
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fierro
authors.forename: Frank G
authors.initials: FG
authors.lastname: Williams
authors.forename: Valeria
authors.initials: V
authors.lastname: Spelta
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Naves
authors.forename: Michelle
authors.initials: M
authors.lastname: Knowles
authors.forename: Josephine
authors.initials: J
authors.lastname: Marsh-Haffner
authors.forename: John P
authors.initials: JP
authors.lastname: Adelman
authors.forename: Wolfhard
authors.initials: W
authors.lastname: Almers
authors.forename: Robert P
authors.initials: RP
authors.lastname: Elde
authors.forename: Edwin W
authors.initials: EW
authors.lastname: McCleskey
mesh_terms: D062565:Acid Sensing Ion Channels; D000140:Acidosis, Lactic / Q000378:metabolism / Q000503:physiopathology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000294:innervation* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058485:Receptors, Purinergic P2X5 / Q000378:metabolism* / Q000502:physiology; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D015222:Sodium Channels / Q000378:metabolism* / Q000502:physiology
chemical_list: C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D058485:Receptors, Purinergic P2X5; D015222:Sodium Channels; D000255:Adenosine Triphosphate