The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulates the Functional Output of Human Taste Bud Cells

Abstract

We recently discovered that the cystic fibrosis transmembrane conductance regulator protein (CFTR), which functions as a channel that transports chloride and bicarbonate across epithelial surfaces, is expressed in both human and murine TBCs, but how it functions in these cells remains unknown. We postulated that CFTR may impact peripheral taste signaling at the level of taste receptor-expressing cells of the taste bud. To begin to test this hypothesis, we assessed how pharmacological manipulation of CFTR could affect the functional responses of human fungiform taste bud cells to prototypical taste stimuli (e.g., bitter, sweet, fat) using single cell calcium imaging and neurotransmitter (ATP) release measurements. We first established the presence of CFTR in these cells using immunocytochemistry and RT-PCR. We next found that CFTR inhibition generally increased stimulus-evoked calcium responses but that the specific response parameters impacted varied across different stimuli, likely due to differences in signal transduction mechanisms and the involvement of store-operated calcium channels. For example, response amplitudes to bitter and sweet stimuli were significantly enhanced with no changes in the proportion of cells responding to these stimuli whereas the opposite trends were observed with a fatty acid stimulus. Additionally, bitter-evoked neurotransmitter release was significantly enhanced by CFTR inhibition, suggesting that this effect is reflected throughout the signal transduction cascade. Ongoing and future experiments are utilizing shRNA knockdown as well as intracellular and extracellular electrophysiology to further interrogate the impacts of CFTR. In addition to human TBCs, we have detected CFTR in mouse taste tissues. Moreover, we have mined mouse TBC RNA sequencing datasets to determine CFTR co-expression patterns to inform future cellular and behavioral experiments in mice. Taken together, these data suggest that CFTR can modulate the signaling output of the taste bud.