Item

Abstract

Disorders of gallbladder motility can lead to serious pathology. Bitter
tastants acting upon bitter taste receptors (TAS2R family) have been
proposed as a novel class of smooth muscle relaxants to combat excessive
contraction in the airways and other organs. To explore whether this
might also emerge as an option for gallbladder diseases, we here tested
bitter tastants for relaxant properties and profiled Tas2r expression in
the mouse gallbladder. In organ bath experiments, the bitter tastants
denatonium, quinine, dextromethorphan, and noscapine, dose-dependently
relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse
strains, neither transient receptor potential family member 5 (TRPM5),
nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved
to be required for this relaxation, indicating direct action upon smooth
muscle cells (SMC). Accordingly, denatonium, quinine and
dextromethorphan increased intracellular calcium concentration
preferentially in isolated gallbladder SMC and, again, this effect was
independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126,
Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice
lacking tuft cells revealed preferential expression of Tas2r108 and
Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft
cells in the gallbladder epithelium. An in silico analysis of a scRNA
sequencing data set revealed Tas2r expression in only few cells of
different identity, and from in situ hybridization histochemistry, which
did not label distinct cells. Our findings demonstrate profound tuft
cell- and TRPM5-independent relaxing effects of bitter tastants on
gallbladder smooth muscle, but do not support the concept that these
effects are mediated by bitter receptors.