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.
Highlights
The transient receptor potential (TRP) family is a group of excitatory cation channels expressed in multiple cell types within the body that act as environmental sensors to noxious chemical, thermal and mechanical stimuli (Ramsey et al, 2006)
colonic peristaltic motor complexes (CPMCs) activity was initiated in individual mouse colonic segments via luminal infusion of Krebs solution and was monitored experimentally as increases in intraluminal pressure (Figure 1A) which propagated in an aboral direction along the whole length of the colon
We tested the effect of the transient receptor potential ankyrin 1 (TRPA1) antagonist HC-030031(1–10 μM) on CPMC activity and found that HC-030031 had no significant effect upon baseline CPMC activity at any of the concentrations tested (Supplementary Figure S1)
Summary
The transient receptor potential (TRP) family is a group of excitatory cation channels expressed in multiple cell types within the body that act as environmental sensors to noxious chemical, thermal and mechanical stimuli (Ramsey et al, 2006). In addition to thermal stimuli, TRPA1 has been shown to be activated by a wide range of chemicals including nutrient derived compounds such as allyl isothiocyanate (AITC), cinnamaldehyde (CMA), and allicin that are found in mustard, cinnamon and garlic, respectively, as well as acrid chemicals including acrolein and tear gas These compounds are believed to activate the channel through a process of modifying specific cysteine or lysine residues contained within the amino terminus of the protein In addition to exogenous agonists, TRPA1 can be activated by endogenous chemicals including 4-hydroxy-2-nonenal (HNE), an inflammatory mediator produced through oxidative stress (Esterbauer et al, 1991) providing evidence that TRPA1 is capable of transducing inflammatory derived signals into cellular responses (Trevisani et al, 2007)
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