ML-SA1, a TRPML1 agonist, induces gastric secretion and gastrointestinal tract inflammation in vivo

Background: The effect of ML-SA1, a potent and specific TRPML1 channel agonist, on gastric secretion and subsequent impact to the gastrointestinal (GI) tract of mice was investigated. Methods: Twenty mice were divided into two groups, and respectively received either ML-SA1 or DMSO alone (as negative control), and then the intestinal propulsion rate were monitored. The stomach and intestinal tissues were sectioned for periodic acid Schiff (PAS), histopathological or immunohistochemical (IHC) analysis. TRPML1 expression level in AGS cells was assayed by western blot, and calcium imaging was performed in AGS cells after the GCaMP5G transfection. Results: Application of 150 μg/Kg ML-SA1 could result in significant decrease in intestinal propulsion rate and structural changes of the parietal cells in stomach and goblet cells in intestine of mice. Moreover, it induced inflammation to the duodenum section of intestine in mice. IHC staining also revealed that ML-SA1 could up-regulate TRPML1 expression in both the parietal cells of stomach pits and in the columnar epithelial cells of duodenum villi. Further study in AGS cells, a type of stomach cell line, demonstrated that ML-SA1 could enhance the expression of TRPML1 and induce the protrusion of micro-vesicles. Conclusions: All together, our results suggested that ML-SA1 was capable of activating TRPML1 in stomach cells and increasing gastric juice secretion. This provided a convincing attempt of applying ML-SA1 in animals and pointed out a new possible research direction that TRPML1 channel could be a potential new therapeutic target on hypochlorhydria or even in the field of gastrointestinal cancer research.