Bitter taste receptor agonists as potent tocolytics for preterm labor

Abstract

Preterm labor (PTL), the leading cause of neonatal mortality and morbidity, occurs in ~11% of pregnancies. Its etiologic mechanisms are complex, multifactorial, and not clearly elucidated. PTL is defined by cervical change in the presence of regular uterine contractions occurring prior to 37 weeks gestation in humans. Given contractions as a central feature, tocolytics are used in its management, yet current tocolytics are not sufficiently effective. In the present study, we report that myometrial cells from mouse and human express bitter taste receptors (TAS2Rs), a class of proteins that were long thought to be solely in the taste buds of tongues, and their canonical signaling components (i.e., G‐protein gustducin and PLCβ2). Strikingly, bitter tastants (e.g., chloroquine) relax myometrium pre‐contracted by uterotonics (e.g., oxytocin and prostaglandin F2α) more completely than current commonly used tocolytics (i.e., nifedipine, indomethacin and MgSO4) and at a lower dose than MgSO4 and indomethacin. Using isolated single mouse myometrial cells, we found that bitter tastants reverse the rise in [Ca2+]i and cell shortening induced by uterotonics, and this reversal effect is inhibited by pertussis toxin treatment and α‐gustducin deletion. Moreover, bitter tastants (e.g., chloroquine) can prevent mouse PTL induced by bacterial endotoxin lipopolysaccharide more often than current commonly used tocolytics. In summary, myometrial cells express the canonical bitter taste receptor signaling system, and bitter tastants demonstrate the potential to be more effective tocolytics than those currently used for PTL management.