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

Abstract

BackgroundDifficulty 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.MethodsWe 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 ResultsWe 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 & InferencesAcid‐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.

Targeting Chemosensory Ion Channels in Peripheral Swallowing-Related Regions for the Management of Oropharyngeal Dysphagia

“…They are expressed on taste buds and epithelial cells of the tongue [ 236 , 237 ], as well as on nerve fibers and epithelial cells in the esophagus [ 233 , 238 , 239 ]. In our animal study, we observed ASIC3 on epithelial cells and afferent nerve fibers in the laryngopharynx and associated laryngeal regions innervated by the SLN [ 117 ]. Moreover, in human biopsy tissues of oropharyngeal regions, ASIC3 expression has been observed in the afferent nerve fibers that innervate the mucosa of the human tongue, pharynx, and lingual surface of the epiglottis [ 227 ].…”

“…Acids can activate both TRPV1 and ASICs. To understand the specific involvement of ASIC channels in swallowing, we recently used non-acid/non-proton activators for ASIC3 in an animal study [ 117 ]. The topical application of a natural (agmatine) and a synthetic (guanidine-4-methylquinazoline) non-proton ASIC3 agonist into the laryngopharynx and associated laryngeal regions dose-dependently facilitated the triggering of swallowing reflexes [ 117 ].…”

“…To understand the specific involvement of ASIC channels in swallowing, we recently used non-acid/non-proton activators for ASIC3 in an animal study [ 117 ]. The topical application of a natural (agmatine) and a synthetic (guanidine-4-methylquinazoline) non-proton ASIC3 agonist into the laryngopharynx and associated laryngeal regions dose-dependently facilitated the triggering of swallowing reflexes [ 117 ]. This faciliatory effect of ASIC3 was significantly suppressed by the prior topical application of an ASIC3 antagonist, suggesting the specific involvement of these channels in the facilitation [ 117 ].…”

“…Along with other peripheral sensory stimulation strategies, peripheral chemical sensory stimulation is effective for facilitating swallowing function, and many recent animal and clinical studies have investigated this strategy [ 44 , 48 , 79 , 82 , 113 , 114 , 115 , 116 , 117 ]. With peripheral chemical sensory stimulation, various chemosensory ion channels that are expressed in peripheral swallowing-related regions are targeted.…”

TRPA1s act as chemosensors but not as cold sensors or mechanosensors to trigger the swallowing reflex in rats

“…The laryngopharyngeal and associated laryngeal regions are richly innervated 40 , 41 . Previous studies, including those from our group, have reported that chemical stimulation of these regions can modulate SLN activity and trigger swallowing reflexes, which suggests an important role for chemosensors 4 , 42 – 46 . In support, several studies including randomized clinical trials in patients with dysphagia have reported improvements in the efficacy, safety, and physiology of swallowing by chemical stimulation in the peripheral swallowing-related regions 4 , 24 , 47 – 53 .…”