An acid-sensing ion channel that detects ischemic pain

Abstract

Ischemic pain occurs when there is insufficient blood flow for the metabolic needs of an organ. The pain of a heart attack is the prototypical example. Multiple compounds released from ischemic muscle likely contribute to this pain by acting on sensory neurons that innervate muscle. One such compound is lactic acid. Here, we show that ASIC3 (acid-sensing ion channel #3) has the appropriate expression pattern and physical properties to be the detector of this lactic acid. In rats, it is expressed only in sensory neurons and then only on a minority (~40%) of these. Nevertheless, it is expressed at extremely high levels on virtually all dorsal root ganglion sensory neurons that innervate the heart. It is extraordinarily sensitive to protons (Hill slope 4, half-activating pH 6.7), allowing it to readily respond to the small changes in extracellular pH (from 7.4 to 7.0) that occur during muscle ischemia. Moreover, both extracellular lactate and extracellular ATP increase the sensitivity of ASIC3 to protons. This final property makes ASIC3 a "coincidence detector" of three molecules that appear during ischemia, thereby allowing it to better detect acidosis caused by ischemia than other forms of systemic acidosis such as hypercapnia.

Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

“…Furthermore, decreases in pH activate acidsensing ion channels (ASICs) (68). The activity of ASIC3, which has been found on sensory neurons innervating muscle (41,61), increases the presence of lactic acid (44). More recently, mRNA for ASIC3 and ASIC1a were detected in whole muscle tissue with the greater expression observed for ASIC3 (23).…”

Acid-sensing ion channel 3 (ASIC3) cell surface expression is modulated by PSD-95 within lipid rafts

“…It localizes to nerve terminals, where it may function as a transducer of various sensory stimuli (35). Modest drops in pH activate ASIC3, and several lines of evidence support its role as a metabolic or pain sensor during acidic conditions: 1) ASIC3 is highly expressed in sensory nerves of cardiac (2,41) and skeletal muscle (31,32), tissues that have high metabolic activity and are thus susceptible to ischemia leading to production and accumulation of lactic acid; 2) lactate anion potentiates the pH sensitivity of ASIC3, providing a molecular explanation for why lactate is a more potent activator of sensory neurons compared with other acids (23); 3) pharmacological blockade of ASICs attenuate acid-induced pain in human skin (24,48); and 4) mice lacking ASIC3 demonstrate diminished pain hypersensitivity in models of chronic hyperalgesia (25,40). In addition to its function as a pH sensor, ASIC3 has been implicated in playing a role in mechanosensation;…”

Morphological and functional diversity of first-order somatosensory neurons

“…Retrograde labeling of dental pulp afferents permitted the identification of a population of nociceptors which was found to contain small, medium, and large diameter cell bodies (Silbert et al 2003). In other studies, expression of ASIC3, a putative nociceptive marker (McCleskey and Gold 1999;Naves and McCleskey 2005), was found in larger neurons that did not express P2X3 currents (Molliver et al 2005;Moraes et al 2014). These large neurons, which respond to reduced pH, lactate, and ATP released during ischemia, may correspond to muscle metaboreceptors or nociceptors Yagi et al 2006;Birdsong et al 2010;Light et al 2008).…”