Sustained Currents Through ASIC3 Ion Channels at the Modest pH Changes That Occur During Myocardial Ischemia

Abstract

Abstract-Acid-sensing ion channel 3 (ASIC3) is highly expressed on sensory neurons that innervate heart and skeletal muscle and, therefore, is proposed to detect lactic acidosis and to transduce angina and muscle ischemic pain. A difficulty with this idea is that ASIC3 rapidly desensitizes. How can a desensitizing ion channel mediate a persisting sensation such as angina? Here, we show that rat ASIC3 produces a sustained current within the limited range of extracellular pH (7.3 to 6.7) that occurs during cardiac and skeletal muscle ischemia; experiments use patch clamp on transfected cell lines and on fluorescently tagged sensory neurons that innervate rat heart. No such sustained current occurs with ASIC1a (either as homomers or 1a/3 heteromers), whereas ASIC2a/3 heteromers give much larger currents than ASIC3 homomers. The sustained current persists even over tens of minutes because it is caused by a region of pH where there is overlap between inactivation and activation of the channel. Lactate, an anaerobic metabolite, allows the current to activate at slightly more basic pH. Surprisingly, amiloride, which blocks ASICs when they are activated at lower pH, increases ASIC3 current evoked at pH 7.0. Cardiac sensory neurons exhibit a small, perfectly sustained current when pH changes from 7.4 to 7.0. At least some of this current is carried by ASICs because the current is increased by both Zn 2ϩ , an ASIC modulator, and amiloride. We suggest that this sustained mode is the most relevant form of ASIC3 gating for triggering angina and other ischemic pain.

Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms

“…In agreement with this, several independent labs have reported that APETx2 is analgesic in rat models of inflammatory and osteoarthritic pain (Deval et al, 2008;Ikeuchi et al, 2009;Karczewski et al, 2010). Peripheral application of APETx2 also reduces mechanical hypersensitivity in non-inflammatory muscular pain models and angina (Ikeuchi et al, 2008;Yagi et al, 2006). In a study assessing the biological stability of APETx2 and cyclised analogues, the wild-type peptide was almost completely broken down in simulated gastric fluid within 20 minutes while the stability in serum was not assessed (Jensen et al, 2012).…”

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…The sustained component of the ASIC3 current, on the other hand, is much less or completely insensitive to amiloride [28,45]. A recent study has shown that in cardiac sensory neurons, the small sustained ASIC3-like current activated at pH 7.0 is in fact increased by amiloride [46].…”

“…Therapeutic potential-Since activation of ASIC3 has been implicated in various pain processes [46,51,62,63], APETx2 may be a useful analgesic agent in the treatment or prevention of pain in peripheral sensory system. However, its lack of inhibition of sustained ASIC3 current suggests that it may not be effective in suppressing the chronic pain stimuli.…”

ASIC3 Channels in Multimodal Sensory Perception

“…The bell-shaped relationship between current amplitude and pH changes suggests that the overall current may result from the combined effects of steady-state activation and desensitization of ASIC3 (39), giving rise to a characteristic "window current" (15,39). Lactic acid increases the pH sensitivity of the window current (39), presumably through a mechanism of chelation of extracellular Ca 2þ (40,41). Furthermore, newly identified nonproton ligands including an endogenous ligand agmatine (13) also significantly enhanced the window current, supporting a specific role of the sustained window current in pathophysiological processes.…”