From the Cover: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons

Abstract

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.

Heparinized chitosan/poly(γ-glutamic acid) nanoparticles for multi-functional delivery of fibroblast growth factor and heparin

“…It has been reported that the ischemic and inflamed areas in the body have a lower pH (<6.7) than the surrounding tissues and blood (pH ¼ 7.4) [24,25]. If a nanoparticle can release bFGF in a sustained way in the ischemic and inflamed areas (pH<6.7), and then rapidly disintegrate after repairing the tissue (pH ¼ 7.4), this nanoparticle might be useful as an intelligent, controlled release material.…”

“…The CS/g-PGA and HP-CS/g-PGA nanoparticles were dispersed in distinct dissolution media (pH 6.0, 6.6 and 7.4 of buffer solutions, simulating the pH environments in ischemia tissue, critical ischemic tissue and normal tissue respectively) [24,25], and the dispersive stabilities of the nanoparticle were evaluated by turbidity measurement using a UVeVis spectrophotometer (Uvikon923, Kontron Instruments, Italy) at 500 nm [26]. The mean particle sizes and zeta potential values of nanoparticles were measured using a Zetasizer as abovementioned method.…”

“…However, myocardial extracellular pH drops from 7.4 to less than 6.7 during severe cardiac ischemia [24]. Brain tissue pH typically falls to 6.0e6.5 during ischemia under normoglycemic conditions and can fall below 6.0 during severe ischemia or under hyperglycemic conditions [25].…”

Acid-Sensing Ion Channels Contribute to Neurotoxicity

“…The transient currents are highly sensitive to protons, with a pH 50 of around 6.5 [65, 69]. Electrophysiological studies have shown that ASIC3 subunits function as homomeric or heteromeric channels in sensory neurons [16, 70–75]. They can sense extracellular acidification occurring under physiological or pathological conditions, such as cutaneous touch, pain perception, inflammation, and ischemia [70, 74, 76–82].…”

“…Electrophysiological studies have shown that ASIC3 subunits function as homomeric or heteromeric channels in sensory neurons [16, 70–75]. They can sense extracellular acidification occurring under physiological or pathological conditions, such as cutaneous touch, pain perception, inflammation, and ischemia [70, 74, 76–82]. For example, ASIC3 channels expressed in cardiac sensory neurons can respond to myocardial ischemia [70, 75, 82].…”