Functional involvement of acid-sensing ion channel 3 in the swallowing reflex in rats

Background: Difficulty swallowing represents a major health problem. Swallowing function is improved by incorporating weak acids in suspensions/food boluses, implicating acid-sensing ion channels (ASICs) in the swallowing reflex. However, the functional involvement of ASICs in the swallowing reflex has not been fully elucidated. Methods: We localized ASIC3s in swallowing-related regions innervated by the superior laryngeal nerves (SLNs) and those in the nodose-petrosal-jugular ganglionic complex (NPJc) and examined their functional involvement in evoking the swallowing reflex in rats. Key Results: We localized ASIC3s on epithelial cells and nerve fibers in swallowing-related regions innervated by the SLNs. In the NPJc, around half of the SLN-afferent neurons expressed ASIC3. Two-thirds of ASIC3s were localized on unmyelinated neurons in the nodose and petrosal ganglia. In the jugular ganglia, they were equally distributed on unmyelinated and myelinated neurons. Topical application of a synthetic non-proton ASIC3 activator, 2-guanidine-4-methylquinazoline (GMQ), and its natural endogenous ligand agmatine (a metabolite of the amino acid arginine) in swallowing-related regions evoked a considerable number of swallowing reflexes. Increasing the concentration of GMQ and agmatine up to a certain concentration increased the number of evoked reflexes and shortened the interval between the evoked reflexes. Agmatine was less potent than GMQ in its ability to evoke swallowing reflexes. Prior topical application of an ASIC3 antagonist significantly attenuated the number of GMQ- and agmatine-evoked swallowing reflexes. Conclusions & Inferences: Acid-sensing ion channel 3s localized on nerves and epithelial cells in swallowing-related regions are functional in evoking the swallowing reflex and activation of these channels via a pharmacological agonist appears to improve swallowing behavior.