Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons.
Cardiac afferents are sensory neurons that mediate angina, pain that occurs when the heart receives insufficient blood supply for its metabolic demand (ischemia). These neurons display enormous acid-evoked depolarizing currents, and they fire action potentials in response to extracellular acidification that accompanies myocardial ischemia. Here we show that acid-sensing ion channel 3 (ASIC3), but no other known acid-sensing ion channel, reproduces the functional features of the channel that underlies the large acid-evoked current in cardiac afferents. ASIC3 and the native channel are both especially sensitive to pH, interact similarly with Ca(2+), and gate rapidly between closed, open, and desensitized states. Particularly important is the ability of ASIC3 and the native channel to open at pH 7, a value reached in the first few minutes of a heart attack. The steep activation curve suggests that the channel opens when four protons bind. We propose that ASIC3, a member of the degenerin channel (of Caenorhabditis elegans)/epithelial sodium channel family of ion channels, is the sensor of myocardial acidity that triggers cardiac pain, and that it might be a useful pharmaceutical target for treating angina.
Sutherland
S P
SP
The Vollum Institute, Oregon Health Sciences University, Portland, OR 97201-3098, USA. sutheris@ohsu.edu
Benson
C J
CJ
Adelman
J P
JP
McCleskey
E W
EW
D062565:Acid Sensing Ion Channels; D000200:Action Potentials; D000344:Afferent Pathways / Q000503:physiopathology; D000787:Angina Pectoris / Q000503:physiopathology*; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D005727:Ganglia, Spinal / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000737:chemistry; D015640:Ion Channel Gating / Q000502:physiology*; D017136:Ion Transport / Q000502:physiology; D008565:Membrane Proteins; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000502:physiology; D011522:Protons; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D014162:Transfection
C112231:ASIC3 protein, human; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011522:Protons; D011993:Recombinant Fusion Proteins; D015222:Sodium Channels; D012964:Sodium; D002118:Calcium