Insights into the therapeutic targeting of ASIC3 in pain: hurdles for clinical development

Acid-sensing ion channel 3 (ASIC3) is a promising therapeutic target for pain because of its unique peripheral expression profile in somatosensory neurons and channel properties for sensing mild extracellular acidosis associated with inflammation, ischemia, and metabolic changes.

As a highly sensitive acid sensor, ASIC3's activity is also enhanced by endogenous modulators in the inflammatory 'soup,' such as arachidonic acid and hypertonicity, and by cold temperatures. Furthermore, ASIC3 activation can be independent of acid changes by molecules such as lysophosphatidylcholine 16:0, a lipid identified as a critical trigger in chronic joint pain and stress-induced widespread pain. Beyond nociception, ASIC3 is strongly implicated in multimodal sensory perception in non-nociceptive neurons. In particular, ASIC3 is expressed in proprioceptors and acts as a mechanical sensor for proprioception via a tether model of mechanotransduction, although direct evidence of tethering elements remains missing. Intriguingly, proprioceptor ASIC3 also plays an important role in acid sensation, called sngception to distinguish the acid-like discomfort (sng, pronounced / səŋ /) from pain sensation.

Therapeutic strategies targeting ASIC3 must account for its intricate molecular crosstalk and unexpected dual role in nociception and sngception as well as its role in maintaining chronic pain and sng.