Activation of bitter taste receptors (tas2rs) relaxes detrusor smooth muscle and suppresses overactive bladder symptoms

Abstract

Bitter taste receptors (TAS2Rs) are traditionally thought to be expressed exclusively on the taste buds of the tongue. However, accumulating evidence has indicated that this receptor family performs non-gustatory functions outside the mouth in addition to taste. Here, we examined the role of TAS2Rs in human and mouse detrusor smooth muscle (DSM). We showed that mRNA for various TAS2R subtypes was expressed in both human and mouse detrusor smooth muscle (DSM) at distinct levels. Chloroquine (CLQ), an agonist for TAS2Rs, concentration-dependently relaxed carbachol- and KCl-induced contractions of human DSM strips. Moreover, 100 μM of CLQ significantly inhibited spontaneous and electrical field stimulation (EFS)-induced contractions of human DSM strips. After a slight contraction, CLQ (1 mM) entirely relaxed carbachol-induced contraction of mouse DSM strips. Furthermore, denatonium and quinine concentration-dependently decreased carbachol-induced contractions of mouse DSM strips. Finally, we demonstrated that CLQ treatment significantly suppressed the overactive bladder (OAB) symptoms of mice with partial bladder outlet obstruction (PBOO). In conclusion, we for the first time provide evidence of the existence of TAS2Rs in the urinary DSM and demonstrate that TAS2Rs may represent a potential target for OAB. These findings open a new approach to develop drugs for OAB in the future.

Olfactory, Taste, and Photo Sensory Receptors in Non-sensory Organs: It Just Makes Sense

“…The TAS2R agonist chloroquine relaxed carbachol-, potassium chloride-, and electrical field stimulation-induced contractions of human detrusor muscle strips in vitro . Denatonium and quinine also decreased carbachol-induced contractions of mouse detrusor muscle strips in a concentration-dependent manner (Zhai et al, 2016 ).…”

“…TAS2Rs have been discovered in both the kidney, where TAS2R105 plays a role in the murine kidney, and the detrusor muscle of the bladder, where it causes bladder relaxation when activated in human subjects (Liu et al, 2015 ; Zhai et al, 2016 ). The TAS2R agonist chloroquine relaxed carbachol-, potassium chloride-, and electrical field stimulation-induced contractions of human detrusor muscle strips in vitro .…”

“…Activation of TAS2Rs leads to smooth muscle relaxation in many different tissue types, providing therapeutic targets to treat diseases like pulmonary hypertension, reactive airway disease (including asthma), and bladder spasms. Medications that target TAS2Rs have mitigated asthma symptoms (Sharma et al, 2017 ) and bladder spasms (Zhai et al, 2016 ) in animal models, but these studies have yet to be repeated in human trials. Studies showing vascular relaxation are limited to vessels in the brain and gastrointestinal tract; however, additional studies should be conducted to determine changes to peripheral and cardiac vasculature.…”

Extraoral bitter taste receptors in health and disease

“…As mentioned previously, activation of T2Rs in urethral chemosensory cells initiates a reflex loop, leading to bladder contraction ( Deckmann et al, 2014 ). In this context, it is interesting that Zhai et al (2016) showed that human and mouse detrusor smooth muscle express T2Rs, and T2R agonists can directly relax precontracted detrusor muscle strips. In vivo study showed that oral gavage of the bitter compound chloroquine suppresses overactive bladder symptoms in mice that possess partial bladder outlet obstruction.…”

Which molecular targets do we need to focus on to improve lower urinary tract dysfunction? ICI‐RS 2017

“…Several other new targets have been suggested to be explored for potential development as treatment options for bladder dysfunction, for example bitter taste receptors (TAS2Rs) …”