# Purinergic Signaling in Swallowing Reflex Initiation: Mechanisms and Therapeutic Implications for Oropharyngeal Dysphagia—A Narrative Review

## TL;DR

This paper reviews how purinergic signaling, specifically ATP release and receptor activation, plays a role in initiating the swallowing reflex and could lead to new treatments for oropharyngeal dysphagia.

## Contribution

The paper highlights purinergic signaling as a novel mechanism for swallowing reflex initiation and suggests its therapeutic potential for dysphagia.

## Key findings

- ATP release from taste buds and neuroendocrine cells activates purinergic receptors to initiate swallowing.
- Pharmacological or genetic disruption of purinergic receptors reduces swallowing reflexes in mice.
- Exogenous ATP or P2X3 agonists can induce swallowing reflexes, indicating therapeutic potential.

## Abstract

The swallowing reflex is a highly coordinated process that is essential for safe bolus transit and airway protection. Although its neurophysiological framework has been extensively studied, the molecular mechanisms underlying reflex initiation remain incompletely understood, limiting targeted therapies for oropharyngeal dysphagia. Recent evidence implicates purinergic signaling as a key mediator of swallowing initiation, particularly through ATP release from taste buds and neuroendocrine cells in the hypopharyngeal and laryngeal mucosa. Experimental studies in mice demonstrate that water, acidic, and bitter chemical stimuli induce ATP release, activating purinergic receptors (P2X2, P2X3, heteromeric P2X2/P2X3, and P2Y1) on afferent sensory fibers. This receptor activation enhances input to the brainstem swallowing central pattern generator, initiating reflexive swallowing. Genetic ablation of purinergic receptor-expressing neurons or epithelial sentinel cells, as well as pharmacological antagonism of P2X or P2X3 receptors, markedly attenuates these responses. Furthermore, exogenous ATP or selective P2X3 agonists applied to swallowing-related mucosa evoke swallowing reflexes in an animal model, underscoring translational potential. While the precise upstream receptor mechanisms for water- and acid-induced ATP release, as well as species-specific differences, remain to be clarified, targeting purinergic pathways may represent a novel physiologically grounded therapeutic strategy for restoring swallowing function in patients with oropharyngeal dysphagia.