Discovery of new sensory cells in the throat and the elucidation of their function

Professor Akiyuki Taruno and his research group at the Graduate School of Medical Science, Kyoto Prefectural University of Medicine, have discovered sensory cells present in very small numbers in the epithelium of the throat. These cells respond to stimuli including bitter plant components, tobacco smoke, air pollutants, and pathogen-derived substances, thereby triggering the mechanisms underlying coughing and swallowing (deglutition), as demonstrated in the study.

A cough lasting more than eight weeks is referred to as chronic cough, with many cases of unknown etiology or refractory to treatment. These research findings will serve as a foundation for elucidating the underlying causes and advancing drug discovery. In addition, the function of these cells may partially account for the characteristic sensation culturally described in Japan as “nodogoshi” when drinking beverages such as beer.

How do coughing and swallowing occur?

The throat is an important site through which food and air pass, and where airway defense reflexes such as coughing and swallowing are activated. If these reactions fail to occur properly, food or saliva may enter the lungs or, conversely, excessive coughing may occur. Chronic cough is a symptom affecting approximately 10% of the global population, with many cases of unknown etiology. It has been known that changes in the condition of the throat can trigger cough and swallowing reflexes, but much of the underlying mechanism has remained unclear.

The research group had previously discovered the channel synapse^*1, a unique intercellular signaling mechanism operating in taste receptor cells of the tongue. Therefore, the idea that this mechanism might also exist in organs other than the tongue served as the impetus for launching this research.

*1 Channel synapse
A mechanism in which electrical stimulation opens ion channels, through which neurotransmitters are released, enabling the rapid transmission of information to nerves.

Cells that detect specific chemical stimuli and trigger coughing and swallowing

Discovery of rare sensory cells in the larynx and pharynx

The research group used genetically modified mice to investigate whether the molecule CALHM1/3^*2, which forms the channel synapses in taste cells, is expressed in other cell types. As a result, CALHM1/3 was found to be expressed in tuft cells of the larynx (Fig. 1) ^*3 and in type II taste receptor cells of the pharyngeal taste buds^*4, with channel synapses also present in these cells. In addition, these two types of cells detected chemical substances on the mucosal surface of the throat and transmit that information to the vagus nerve.

Detecting chemical substances and triggering airway defense reflexes

Analysis of these two cell types revealed that both express the T2R^*5 receptors. T2Rs are molecules that detect dangerous chemical substances for the human body, such as plant toxins, tobacco smoke, airborne pollutants, and pathogen-derived components. When T2Rs detect specific chemical substances, action potentials are generated, and ATP^*6 is released through channel synapses. Next, this neurotransmitter excites the vagus nerve, triggering cough and swallowing reflexes (Fig. 2).

Fig. 2 Mechanism of the channel synapse

In mice lacking the Calhm3 gene, this reaction did not occur, demonstrating the link between molecular-level activity and the reflex response.

Furthermore, another experiment revealed that tuft cells in the larynx are responsible for the cough reflex, while type II taste receptor cells in the pharynx are responsible for the swallowing reflex, respectively.

*5 T2Rs
Receptors that detect bitter-tasting substances and other chemical stimuli. Abbreviation for Type 2 taste receptor

*6 ATP
Adenosine triphosphate, one of the neurotransmitters. Abbreviation for adenosine triphosphate

Involvement in allergic cough hypersensitivity

Several days after intratracheal administration of mold antigen in mice, the cough reflex elicited by T2R stimulation was enhanced; however, this phenomenon was not observed in Calhm3-deficient mice. These findings demonstrate that tuft cells are deeply involved in cough symptoms characteristic of allergic cough hypersensitivity.

Expectations for new treatments and scientific elucidation of throat sensation

This study has demonstrated the existence of a new sensory organ mediating coughing and swallowing, with its function elucidated at the molecular level. In the future, new avenues may emerge for the diagnosis and treatment of chronic cough. Furthermore, the mechanism demonstrated in this study—in which “bitter substances promote swallowing”—may offer a scientific basis for the characteristic sensation culturally described in Japan as “nodogoshi” experienced when drinking beer.