Bitter taste receptors as targets for tocolytics in preterm labor therapy

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 ( 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 Ca concentration ([Ca]) 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 [Ca] 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.

Toward the Identification of Extra-Oral TAS2R Agonists as Drug Agents for Muscle Relaxation Therapies via Bioinformatics-Aided Screening of Bitter Compounds in Traditional Chinese Medicine

“…Therefore, identifying novel targets for tocolytics are essential for more successful management of PTB. In a recent study, it has been shown that in human and mouse USMCs, TAS2R4, 5, 10, 13, 14 and their canonical signaling components (gustducin, PLCβ) are expressed (Zheng et al, 2017). Furthermore, bitter compound, ChQ at 10 mM can induce [Ca 2+ ] i rise and completely relax human USMCs pre-contracted by different uterotonics, which is mediated though TAS2R14 but not TAS2R10.…”

“…For example, bitter taste substances such as quinine can cause airway smooth muscle relaxation, which may be useful for asthma treatment (Deshpande et al, 2010). Studies have also revealed that TAS2Rs mediate relaxation of smooth muscle in other organs such as bladder (Zhai et al, 2016), blood vessel (Manson et al, 2014), and uterus (Zheng et al, 2017). Therefore, TAS2Rs may be novel targets for screening and thus discovering new drug agents for muscle relaxation therapies to treat various diseases (Kim et al, 2018).…”

Personalized expression of bitter ‘taste’ receptors in human skin

“…The results of several studies have demonstrated that the extraoral expression of TAS2Rs is involved in or regulate important biological processes germane to the nature of the tissue in which they reside. Bitter receptors have been implicated in the relaxation of smooth muscle, vasoconstriction, gut motility, bronchodilation, nutrient sensing, insulin release, and the release of the antimicrobial peptide, β-defensin [ 3 – 7 ]. As an example, studies performed by Lee et al .…”

Clinical Role of Extraoral Bitter Taste Receptors

“…Zheng et al studied the problem of preterm birth focusing their work on finding new molecular targets that might mediate myometrial relaxation and possibilities for developing new classes of effective and safe tocolytics [ 32 ]. Considering that TAS2R receptors are an attractive target for smooth muscle relaxants Zheng studied their expression in human myometrium cells obtained from peripartum hysterectomies performed on multiparous reproductive-age women at the time of indicated deliveries for medical reasons (i.e., placenta accreta, postpartum hemorrhage resulting from uterine atony) and cultured hTERT-HM cells.…”