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FASEB J. 2017 Sep;31(9):4037-4052. doi: 10.1096/fj.201601323RR. Epub 2017 May 30.

Bitter taste receptors as targets for tocolytics in preterm labor therapy.

Author information

1
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
2
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
3
Department of Obstetrics and Gynecology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
4
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
College of Pharmacy, University of Rhode Island, Kingstown, Rhode Island, USA.
6
Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
7
Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
8
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China; fxshi@njau.edu.cn.
9
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA; ronghua.zhuge@umassmed.edu.

Abstract

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 β2). 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 α-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 α-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.-Zheng, K., Lu, P., Delpapa, E., Bellve, K., Deng, R., Condon, J. C., Fogarty, K., Lifshitz, L. M., Simas, T. A. M., Shi, F., ZhuGe, R. Bitter taste receptors as targets for tocolytics in preterm labor therapy.

KEYWORDS:

G-protein coupled receptor; chloroquine; relaxation; uterine smooth muscle

PMID:
28559440
PMCID:
PMC5572693
DOI:
10.1096/fj.201601323RR
[Indexed for MEDLINE]
Free PMC Article

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