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 curren ts, and they fire action potentials in response to extracellular acidificat ion that accompanies myocardial ischemia. Here we show that acid-sensing io n channel 3 (ASIC3), but no other known acid-sensing ion channel, reproduce s the functional features of the channel that underlies the large acid-evok ed current in cardiac afferents. ASIC3 and the native channel are both espe cially sensitive to pH, interact similarly with Ca2+, and gate rapidly betw een closed, open, and desensitized states. Particularly important is the ab ility of ASIC3 and the native channel to open at pH 7, a value reached in t he 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 me mber of the degenerin channel (of Caenorhabditis elegans)/epithelial sodium channel family of ion channels, is the sensor of myocardial acidity that t riggers cardiac pain, and that it might be a useful pharmaceutical target f or treating angina.