Calcium-Sensing Receptor and Transient Receptor Ankyrin-1 Mediate Emesis Induction by Deoxynivalenol (Vomitoxin).
The common foodborne mycotoxin deoxynivalenol (DON, vomitoxin) can negatively impact animal and human health by causing food refusal and vomiting. Gut enteroendocrine cells (EECs) secrete hormones that mediate DON's anorectic and emetic effects. In prior work utilizing a cloned EEC model, our laboratory discovered that DON-induced activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor (GPCR), and transient receptor ankyrin-1 (TRPA1), a transient receptor potential (TRP) channel, drives Ca2+-mediated hormone secretion. Consistent with these in vitro findings, CaSR and TRPA1 mediate DON-induced satiety hormone release and food refusal in the mouse, an animal model incapable of vomiting. However, the roles of this GPCR and TRP in DON's emetic effects remain to be determined. To address this, we tested the hypothesis that DON triggers emesis in mink by activating CaSR and TRPA1. Oral gavage with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate; AITC) rapidly elicited emesis in the mink in dose-dependent fashion. Oral pretreatment of the animals with the CaSR antagonist NPS-2143 or the TRP antagonist ruthenium red (RR), respectively, inhibited these responses. Importantly, DON-induced emesis in mink was similarly inhibited by oral pretreatment with NPS-2143 or RR. In addition, these antagonists suppressed concurrent DON-induced elevations in plasma peptide YY3-36and 5-hydroxytryptamine-hormones previously demonstrated to mediate the toxin's emetic effects in mink. Furthermore, antagonist co-treatment additively suppressed DON-induced emesis and peptide YY3-36release. To summarize, the observations here strongly suggest that activation of CaSR and TRPA1 might have critical roles in DON-induced emesis.
College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, People's Republic of China.|Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824.
Wenda
W
Wu
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824.
Hui-Ren
HR
Zhou
Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.|Department of Animal Science, Michigan State University, East Lansing, Michigan 48824.
Steven J
SJ
Bursian
Department of Animal Science, Michigan State University, East Lansing, Michigan 48824.
Jane E
JE
Link
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824; pestka@msu.edu.|Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.|Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824.
James J
JJ
Pestka
D000818:Animals; D017487:Ankyrins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008907:Mink; D044169:Receptors, Calcium-Sensing / Q000502:physiology*; D014255:Trichothecenes / Q000633:toxicity*; D014839:Vomiting / Q000139:chemically induced*
C491707:Ank1 protein, mouse; D017487:Ankyrins; D044169:Receptors, Calcium-Sensing; D014255:Trichothecenes; C007262:deoxynivalenol
5-HT.; PYY3-36; calcium-sensing receptor; deoxynivalenol; emesis; mycotoxin; peptide YY3-36; serotonin; transient receptor potential channel
Am J Gastroenterol. 2000 Oct;95(10):2698-709
11051338
Toxicology. 2000 Nov 16;153(1-3):189-201
11090957
J Pharmacol Exp Ther. 2001 Oct;299(1):323-31
11561095
Am J Med. 2001 Dec 3;111 Suppl 8A:106S-112S
11749934
Biochem Biophys Res Commun. 2003 Nov 28;311(4):915-9
14623268
J Neurosci. 2005 Apr 20;25(16):4052-61
15843607
Endocrinology. 2006 Jan;147(1):3-8
16166213
Auton Neurosci. 2006 Apr 30;125(1-2):100-15
16556512
J Food Prot. 2006 Jul;69(7):1690-8
16865905
Arq Bras Endocrinol Metabol. 2006 Aug;50(4):628-39
17117288
Am J Physiol Endocrinol Metab. 2007 Apr;292(4):E1062-8
17148749
J Clin Endocrinol Metab. 2007 May;92(5):1754-7
17341568
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13525-30
17686976
Mol Pharmacol. 2009 Jun;75(6):1262-79
19297520
Mol Cell Endocrinol. 2010 Mar 25;316(2):120-8
19563862
Eur J Pharmacol. 2009 Sep 1;617(1-3):124-9
19576208
Naunyn Schmiedebergs Arch Pharmacol. 2009 Oct;380(4):353-7
19629446
Nat Neurosci. 2009 Oct;12(10):1293-9
19749751
Biochem Pharmacol. 2010 Jul 1;80(1):113-21
20226176
J Mol Endocrinol. 2010 Oct;45(4):245-56
20682641
Arch Toxicol. 2010 Sep;84(9):663-79
20798930
Curr Biol. 2011 Feb 22;21(4):316-21
21315593
Can J Physiol Pharmacol. 1990 Feb;68(2):230-6
2178747
Can J Physiol Pharmacol. 1990 Feb;68(2):289-93
2178752
Adv Exp Med Biol. 2012;740:103-42
22453940
Cell Metab. 2012 Apr 4;15(4):421-31
22482725
Clin Biochem. 2012 Aug;45(12):943-53
22503956
Toxicol Sci. 2013 Jan;131(1):279-91
22997060
Pflugers Arch. 2012 Nov;464(5):425-58
23001121
J Anim Sci. 2013 May;91(5):1946-56
23230119
Toxicol Sci. 2013 May;133(1):186-95
23457120
PLoS One. 2013 Apr 10;8(4):e60537
23593236
PLoS One. 2013 Aug 21;8(8):e71603
23990963
Eur J Pharmacol. 2014 Jan 5;722:108-21
24157981
Toxicol Sci. 2014 Nov;142(1):167-81
25173790
Toxicol Sci. 2015 Jun;145(2):407-17
25787141
Arch Toxicol. 2016 Apr;90(4):997-1007
25855062
J Appl Physiol (1985). 2015 Jun 15;118(12):1533-43
25858491
Prog Neurobiol. 1989;32(5):351-90
2660187
Arch Toxicol. 2017 Jan;91(1):495-507
26979077
Peptides. 1989 Jan-Feb;10(1):21-4
2748419
Cancer Treat Rev. 1987 Dec;14(3-4):333-6
2964267
Baillieres Clin Gastroenterol. 1988 Jan;2(1):141-68
3289638
Appl Microbiol. 1973 Dec;26(6):1008-10
4767291
J Pharm Pharmacol. 1994 Jul;46(7):553-7
7996381
Neurochem Int. 1997 Feb;30(2):137-47
9017661
J Clin Invest. 1997 Dec 15;100(12):2977-83
9399943