Abstract
Acid sensing ion channel 3 (ASIC3) is highly expressed on the cardiac afferents and has been proposed to transduce the tissue acidification caused by myocardial ischemia into electrical signals leading to chest pain (angina). However, this proposal requires that ASIC3 has certain kinetic properties. Occlusion of a coronary artery for several minutes decreases myocardial tissue pH just to ∼7.0 or 6.7 at the lowest. Thus, the acid sensor must respond within this critical range of extracellular pH. Furthermore, ASIC3 channels desensitize, whereas the chest pain is persistent. Here we show that the small changes in pH do indeed trigger sustained ASIC3 current associated with persistent neuronal excitation expected during angina. Successive 20-sec step changes in pH between 7.4 and 6.7 produced the sustained Na+-selective current in ASIC3-transfected CHO cells. The peak magnitude of the sustained current occurred at pH 7.0. The bell-like shape of the I-pH relationship suggests that the sustained ASIC3 current is a 'window current', caused by overlap of activation and desensitization curves. Lactate, an anaerobic metabolite, enhanced the sustained current at pH 7.2 and 7.1, but not at pH 7.0-6.8. Thus, ASIC3 has appropriate properties to trigger lactic acid-induced nociception during cardiac ischemia. When ASIC3 is co-expressed with ASIC2a, the activation curve shifts to more acidic pH. Thus, the presence of homomers and heteromers of ASIC3 channels provides a cell the ability to generate prolonged current in response to a range of pH below 7.2. [Jpn J Physiol 55 Suppl:S10 (2005)]
