Sodium-Permeable Ion Channels TRPM4 and TRPM5 are Functional in Human Gastric Parietal Cells in Culture and Modulate the Cellular Response to Bitter-Tasting Food Constituents.

Gastric parietal cells secrete chloride ions and protons to form hydrochloric acid. Besides endogenous stimulants, e.g., acetylcholine, bitter-tasting food constituents, e.g., caffeine, induce proton secretion via interaction with bitter taste receptors (TAS2Rs), leading to increased cytosolic Ca2+ and cAMP concentrations. We hypothesized TAS2R activation by bitter tastants to result in proton secretion via cellular Na+ influx mediated by transient receptor potential channels (TRP) M4 and M5 in immortalized human parietal HGT-1 cells. Using the food-derived TAS2R agonists caffeine and l-arginine, we demonstrate both bitter compounds to induce a TRPM4/M5-mediated Na+ influx, with EC50 values of 0.65 and 10.38 mM, respectively, that stimulates cellular proton secretion. Functional involvement of TAS2Rs in the caffeine-evoked effect was demonstrated by means of the TAS2R antagonist homoeriodictyol, and stably CRISPR-Cas9-edited TAS2R43ko cells. Building on previous results, these data further support the suitability of HGT-1 cells as a surrogate cell model for taste cells. In addition, TRPM4/M5 mediated a Na+ influx after stimulating HGT-1 cells with the acetylcholine analogue carbachol, indicating an interaction of the digestion-associated cholinergic pathway with a taste-signaling pathway in parietal cells.

[6]-Gingerol Facilitates CXCL8 Secretion and ROS Production in Primary Human Neutrophils by Targeting the TRPV1 Channel.

SCOPE: Clarifying the function of sensory active TRP (transient receptor potential) channels in non-sensory tissue is of growing interest, especially with regard to food ingredients in nutritionally relevant concentrations. The study hypothesizes the TRPV1 agonist [6]-gingerol to facilitate cellular immune responses of primary human neutrophils, after treatment with 50 nM, a concentration that can be reached in the circulation after habitual dietary intake. METHODS AND RESULTS: qRT-PCR analyses reveal a high abundancy of TRP channel RNA expression in the types of primary leukocytes investigated, namely neutrophils, monocytes, NK cells, T cells, and B cells. Incubation of neutrophils with 50 nM of the known TRPV1 ligand [6]-gingerol led to increased surface expression of CD11b, CD66b, and the fMLF receptor FPR1, as shown by flow cytometry. Upon subsequent stimulation with fMLF, the neutrophils display an about 30% (p < 0.05) increase in CXCL8 secretion as well as in ROS production. Pharmacological inhibition of TRPV1 by trans-tert-butylcyclohexanol abolishes the [6]-gingerol induced effects. CONCLUSIONS: The TRPV1 channel is functionally expressed in human neutrophils. Activation of the channel with [6]-gingerol as a food-derived ligand in nutritionally relevant concentrations leads to an enhanced responsiveness in the cells towards activating stimuli, thereby facilitating a canonical cellular immune response in human neutrophils.

The SLC26A9 inhibitor S9-A13 provides no evidence for a role of SLC26A9 in airway chloride secretion but suggests a contribution to regulation of ASL pH and gastric proton secretion.

The solute carrier 26 family member A9 (SLC26A9) is an epithelial anion transporter that is assumed to contribute to airway chloride secretion and surface hydration. Whether SLC26A9 or CFTR is responsible for airway Cl- transport under basal conditions is still unclear, due to the lack of a specific inhibitor for SLC26A9. In the present study, we report a novel potent and specific inhibitor for SLC26A9, identified by screening of a drug-like molecule library and subsequent chemical modifications. The most potent compound S9-A13 inhibited SLC26A9 with an IC50 of 90.9 ± 13.4 nM. S9-A13 did not inhibit other members of the SLC26 family and had no effects on Cl- channels such as CFTR, TMEM16A, or VRAC. S9-A13 inhibited SLC26A9 Cl- currents in cells that lack expression of CFTR. It also inhibited proton secretion by HGT-1 human gastric cells. In contrast, S9-A13 had minimal effects on ion transport in human airway epithelia and mouse trachea, despite clear expression of SLC26A9 in the apical membrane of ciliated cells. In both tissues, basal and stimulated Cl- secretion was due to CFTR, while acidification of airway surface liquid by S9-A13 suggests a role of SLC26A9 for airway bicarbonate secretion.