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The global prevalence of GERD is substantially increasing each year, and GERD is a chronic disease that reduces the quality of life of patients. The efficacy of conventional drugs is diverse, and most require long‐term or lifetime administration; thus, the development of more effective therapeutic agents is needed. Herein, a more effective treatment for GERD was tested. We investigated whether JP‐1366 affected gastric H+/K+‐ATPase activity and used the Na+/K+‐ATPase assay to confirm the selectivity of H+/K+‐ATPase inhibition. To clarify the mechanism of enzyme inhibition, JP‐1366 and TAK‐438 were analyzed by Lineweaver–Burk. Also, we investigated the effects of JP‐1366 in various models involving reflux esophagitis. We found that JP‐1366 mediates strong, selective, and dose‐dependent inhibition of H+/K+‐ATPase. We found that JP‐1366 significantly suppressed gastric acid secretion in histamine‐treated pylorus‐ligated rats in a dose‐dependent manner. Additionally, we confirmed that JP‐1366 inhibited histamine‐stimulated gastric acid secretion in the HPD model. JP‐1366 exhibited a more than 2‐fold higher inhibitory effect on esophageal injury than TAK‐438 in GERD lesions and had a more potent inhibitory effect in indomethacin‐ or aspirin‐induced gastric ulcer rat models than TAK‐438. Additionally, JP‐1366 inhibited gastric ulcers. These results support the possibility that JP‐1366 is a good candidate drug for treating acid‐related diseases. [ABSTRACT FROM AUTHOR]

At the time of fertilization, an increase in the intracellular Ca2+ concentration ([Ca2+]i) underlies egg activation and initiation of development in all species studied to date. The inositol 1,4,5-trisphosphate receptor (IP3R1), which is mostly located in the endoplasmic reticulum (ER) mediates the majority of this Ca2+ release. The sensitivity of IP3R1, that is, its Ca2+ releasing capability, is increased during oocyte maturation so that the optimum [Ca2+]i response concurs with fertilization, which in mammals occurs at metaphase of second meiosis. Multiple IP3R1 modifications affect its sensitivity, including phosphorylation, sub-cellular localization, and ER Ca2+ concentration ([Ca2+]ER). Here, we evaluated using mouse oocytes how each of these factors affected IP3R1 sensitivity. The capacity for IP3-induced Ca2+ release markedly increased at the germinal vesicle breakdown stage, although oocytes only acquire the ability to initiate fertilization-like oscillations at later stages of maturation. The increase in IP3R1 sensitivity was underpinned by an increase in [Ca2+]ER and receptor phosphorylation(s) but not by changes in IP3R1 cellular distribution, as inhibition of the former factors reduced Ca2+ release, whereas inhibition of the latter had no impact. Therefore, the results suggest that the regulation of [Ca2+]ER and IP3R1 phosphorylation during maturation enhance IP3R1 sensitivity rendering oocytes competent to initiate oscillations at the expected time of fertilization. The temporal discrepancy between the initiation of changes in IP3R1 sensitivity and acquisition of mature oscillatory capacity suggest that other mechanisms that regulate Ca2+ homeostasis also shape the pattern of oscillations in mammalian eggs. J. Cell. Physiol. 227: 705-717, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]