Agonists of orally expressed TRP channels stimulate salivary secretion and modify the salivary proteome

Abstract

41Natural compounds that can stimulate salivary secretion are of interest in developing treatments for 42 xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly 43 population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of 44 the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary 45 flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists 46 have not been investigated. In this study we have determined the influence of different TRP channel 47 agonists on the flow and protein composition of saliva. 48 49Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole 50 mouth saliva (WMS) flow and total protein secretion compared to unstimulated saliva, the vehicle control 51 mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor 52 gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on 53 the composition and function of the salivary proteome was investigated using a multi-batch quantitative 54 mass spectrometry method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation 55 was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation 56 was identified with some of the mouth rinses. Significant changes in specific salivary proteins were 57 identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional 58 shifts in the WMS secreted, primarily the over representation of salivary and non-salivary cystatins 59 which was confirmed by immunoassay. 60 61This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and 62 the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel 63 agonists are potential candidates for developing treatments for sufferers of xerostomia.

Expression and distribution of the transient receptor potential cationic channel ankyrin 1 (TRPA1) in the human seminal vesicles

“…The location of TRPA1 in the epithelium forms a morphological basis for the involvement in secretory function. Interestingly, cinnamonaldehyde has been shown to alter both the flow rate and composition of salivary gland secretions in human volunteers 27 . Up until today, TRPA1 has been investigated in other male and female genital tissues: In the human clitoris and vagina, TRPA1 was shown to be expressed in slender varicose nerve fibers transversing subepithelial layers.…”

“…Interestingly, cinnamonaldehyde has been shown to alter both the flow rate and composition of salivary gland secretions in human volunteers. 27 Up until today, TRPA1 has been investigated in other male and female genital tissues: In the human clitoris and vagina, TRPA1 was shown to be expressed in slender varicose nerve fibers transversing subepithelial layers. These nerves were also immunoreactive for nNOS and, in the vaginal wall, the CGRP.…”

Disease-Induced Changes in Salivary Gland Function and the Composition of Saliva

“…Parotid gland secretion is strongly influenced by mastication while different smells associated with food can evoke submandibular/sublingual gland secretion. Saliva is also secreted in response to trigeminal chemosensory stimulation of transient receptor potential (TRP) V1 and TRPM8 channels, by agonists such as capsaicin and menthol (Houghton et al 2020). Central integration of sensory nerve signals in the salivary nuclei is subject to regulation by stimulatory or inhibitory signals descending from the cortical centers in the brain (Fig.…”

“…The nature of the reflex stimulus may also influence the composition of saliva. Changes in the proteome of whole-mouth saliva following trigeminal nerve-stimulating agonists have been revealed (Houghton et al 2020). Bitter and other taste modalities and phenolic astringency have been found to cause acute changes in the salivary proteome (Neyraud et al 2006).…”