Bitter taste receptors as targets for tocolytics in preterm labor therapy
Authors
Zheng, KaizhiLu, Ping
Delpapa, Ellen
Bellve, Karl D.
Deng, Ruitang
Condon, Jennifer C.
Fogarty, Kevin E.
Lifshitz, Lawrence M.
Moore Simas, Tiffany A.
Shi, Fangxiong
ZhuGe, Ronghua
UMass Chan Affiliations
Program in Molecular MedicineDepartment of Microbiology and Physiological Systems
Department of Obstetrics and Gynecology
Document Type
Journal ArticlePublication Date
2017-09-01Keywords
Cellular and Molecular PhysiologyFemale Urogenital Diseases and Pregnancy Complications
Maternal and Child Health
Obstetrics and Gynecology
Reproductive and Urinary Physiology
Women's Health
Metadata
Show full item recordAbstract
Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity, with few prevention and treatment options. Uterine contraction is a central feature of PTB, so gaining new insights into the mechanisms of this contraction and consequently identifying novel targets for tocolytics are essential for more successful management of PTB. Here we report that myometrial cells from human and mouse express bitter taste receptors (TAS2Rs) and their canonical signaling components (i.e., G-protein gustducin and phospholipase C beta2). Bitter tastants can completely relax myometrium precontracted by different uterotonics. In isolated single mouse myometrial cells, a phenotypical bitter tastant (chloroquine, ChQ) reverses the rise in intracellular Ca2+ concentration ([Ca2+]i) and cell shortening induced by uterotonics, and this reversal effect is inhibited by pertussis toxin and by genetic deletion of alpha-gustducin. In human myometrial cells, knockdown of TAS2R14 but not TAS2R10 inhibits ChQ's reversal effect on an oxytocin-induced rise in [Ca2+]i Finally, ChQ prevents mouse PTBs induced by bacterial endotoxin LPS or progesterone receptor antagonist mifepristone more often than current commonly used tocolytics, and this prevention is largely lost in alpha-gustducin knockout mice. Collectively, our results reveal that activation of the canonical TAS2R signaling system in myometrial cells produces profound relaxation of myometrium precontracted by a broad spectrum of contractile agonists, and that targeting TAS2Rs is an attractive approach to developing effective tocolytics for PTB management.Source
FASEB J. 2017 Sep;31(9):4037-4052. doi: 10.1096/fj.201601323RR. Epub 2017 May 30. Link to article on publisher's siteDOI
10.1096/fj.201601323RRPermanent Link to this Item
http://hdl.handle.net/20.500.14038/42770PubMed ID
28559440Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1096/fj.201601323RR