Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin)

Abstract

Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON's anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist's effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY (PYY); cotreatment with both antagonists additively suppressed both anorectic and hormone responses to DON. Taken together, these in vivo data along with prior in vitro findings support the contention that activation of CaSR and TRPA1 contributes to DON-induced food refusal by mediating satiety hormone exocytosis from EEC.

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

“…The CaSR may also exert these anorectic effects by increasing the secretion of GLP-1210, which in turn suppresses appetite following food ingestion, as well as by increasing CCK secretion from I-cells220, that leads to a delay in gastric emptying. CaSR activation may also cause emesis and studies involving mice have demonstrated that deoxynivalenol, which is an emesis-inducing toxin, acts by increasing CaSR-mediated secretion of CCK and PYY221. These findings may potentially explain the GI adverse effects such as nausea and vomiting, which are experienced by >30% of patients being treated with cinacalcet, which is used for pharmacological activation of the CaSR 146.…”

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19

“…Loss of appetite is common [46] and may be severe in COVID- 19. It has been suggested that TRPA1 may play a role in food intake and satiety [47][48][49][50]. In animals, TRPA1 activation increases appetite [51].…”

TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity—A Structured Review

“…The frequent contamination of wheat with the fungi Fusarium leads to food contamination by trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) [ 109 ]. DON suppresses food intake and thereby affects energy balance, which is a major concern in human and animal health.…”

“…The exocytosis of satiety hormones like cholecystokinin and peptide YY 3–36 is induced by DON-activated calcium-sensing receptor (CaSR) and TRPA1-mediated Ca 2+ entry into enteroendocrine cells [ 110 ]. Further analysis of the role of CaSR and TRPA1 in the observed anorexia and emesis will shed light on the underlying mechanisms, and can therefore serve as a model to understand comparable symptoms induced by other foodborne toxins, environmental toxicants and chemotherapeutic drugs [ 109 ].…”