{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Acid‐sensing ion channel 3 (ASIC3) is a proton‐gated cation channel predominantly expressed in sensory neurons that plays a multifaceted role in mediating mechanosensation and nociception under both physiological and pathological conditions. ASIC3 contributes to the detection of mechanical stimuli in visceral tissues such as the colon, where its expression in afferent fibers is essential for normal mechanotransduction and the development of nociceptive responses during distension, as evidenced by diminished visceromotor responses in ASIC3 knockout mice."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, ASIC3 modulates pain signaling in inflammatory settings; studies in joint and muscle inflammation have shown that while primary hyperalgesia may be preserved, the development of secondary hyperalgesia critically depends on ASIC3 activation and upregulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " Furthermore, ASIC3 is implicated in the detection of ischemic signals in muscle through its sensitization by ATP—released during ischemia—to enhance the channel’s pH sensitivity, thereby contributing to ischemic pain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its inflammatory functions, ASIC3 is involved in diverse mechanosensory roles: it participates in dynamic mechanotransduction in proprioceptors, influencing muscle spindle afferent responses and motor coordination"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and it contributes to cardiac pain sensation by forming heteromeric channels with ASIC2a in dorsal root ganglion neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " At the molecular level, ASIC3 function is finely tuned by post-translational and modulatory mechanisms such as phosphorylation (involving protein kinase C and the silent ASIC2b subunit) that shift its pH sensitivity, as well as by lipid mediators like lysophosphatidylcholine and arachidonic acid, which can activate ASIC3 even at physiological pH to evoke pain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, human ASIC3 exhibits a dual gating capacity by responding both to acidification and to alkalization, underscoring its dynamic role as a sensor of extracellular pH changes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies establish ASIC3 as a critical peripheral sensor that integrates chemical (pH and lipid) and mechanical signals to modulate nociceptive pathways in various tissues. Its contribution to inflammatory hyperalgesia, ischemic pain, and mechanotransduction in both visceral and somatic systems highlights ASIC3 as a promising therapeutic target for conditions such as irritable bowel syndrome, arthritis, and cardiac pain."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "R Carter W Jones, Linjing Xu, G F Gebhart "}, {"type": "b", "children": [{"type": "t", "text": "The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.0703-05.2005"}], "href": "https://doi.org/10.1523/JNEUROSCI.0703-05.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16306411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16306411"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Patrick A Hughes, Stuart M Brierley, Richard L Young, et al. 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