TRPA1 Channel Activation Inhibits Motor Activity in the Mouse Colon

Abstract

There is a growing awareness of the role that TRP channels play in regulating sensory and motor functions in the gastrointestinal tract. In this study we used an in-vitro murine model of colonic peristaltic-like complexes (CPMCs) to evaluate the role of exogenous and endogenous TRPA1 signaling processes in regulating colonic motility. Using in-vitro recordings of intraluminal pressure to monitor the presence of CPMCs in colonic segments we performed a series of experiments on male CD1 mice (2 months of age) and found that CPMC activity was attenuated by TRPA1 agonists. Bath application of the TRPA1 antagonist HC-030031 had no effect upon basal CPMC activity whereas application of the synthetic TRPA1 agonist ASP7663 caused a reversible dose dependent decrease in CPMC frequency that was blocked by HC-030031. Cinnamaldehyde and 4-hydroxy-2-nonenal elicited long lasting decreases in CPMC frequency that were blocked by HC-030031 whereas the decreased CPMC activity invoked by AITC could not be blocked by HC-030031. Our results show that any potential mechanosensory function of TRPA1 doesn't involve contributing to distension induced colonic motor activity and that a role for TRPA1 in the colon is through regulating motility through exogenous and endogenous agonist induced inhibitory effects.

Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets

“…The activation of TRPA1 results in the release of serotonin from enterochromaffin cells, which influences gut reflexes and motility ( Nozawa et al, 2009 ). Activation of TRPA1 in gut sensory neurons can influence gut reflexes, including peristalsis (the movement of food through the digestive tract) and sensitivity to the mechanical and chemical stimuli ( Nozawa et al, 2009 ; Hassan et al, 2020 ). Inflammatory mediators such as aldehydes 4-hydroxy-2-hexenal (HHE) and malondialdehyde are released during gut inflammation; increased levels of aldehydes sensitize TRPA1, thereby lowering its activation threshold ( Lennertz et al, 2012 ; Larsson et al, 2016 ).…”

“…TRPA1-mediated signals play a crucial role in coordinating smooth muscle contractions and ensuring the propulsive movements necessary for effective digestion and nutrient absorption ( Cho et al, 2014 ). TRPA1 is present in enterochromaffin (EC) cells within the enteric mucosa, displaying a graded expression profile along the length of the gut and is notably absent from the colon ( Cho et al, 2014 ; Hassan et al, 2020 ).…”

“…Psychological factors play a significant role in causing gastrointestinal disorders ( Wilhelmsen, 2000 ). Stress and anxiety can modulate TRPA1 activity, potentially exacerbating symptoms in individuals with TRPA1 dysregulation and contributing to the complex interplay between the gut and brain ( Hassan et al, 2020 ; Giacco et al, 2023 ; Sullivan et al, 2023 ). Understanding the link between TRPA1 dysregulation and GI disorders opens new avenues for targeted therapeutic interventions.…”

“…In the gastrointestinal tract, TRPA1 exhibits a dynamic expression pattern in various segments, including enteric neurons ( Cho et al, 2014 ; Hassan et al, 2020 ), epithelial cells ( Kono et al, 2013 ), and immune cells ( Naert et al, 2021 ). Activation of TRPA1 in gut sensory neurons influences peristalsis and sensitivity to mechanical and chemical stimuli, and plays a crucial role in gastrointestinal motility ( Tsuchiya and Kawamata, 2019 ).…”