Inhibition of the human secretory pathway Ca2+, Mn2+–ATPase1a by 1,3-thiazole derivatives

• Published in: Biochemical and biophysical research communications Vol. 614; pp. 56 - 62
• Main Authors: Yamamoto-Hijikata, Sachiko, Suga, Kei, Homareda, Haruo, Ushimaru, Makoto
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 23.07.2022
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.05.010

The human Golgi/secretory pathway Ca2+,Mn2+-ATPase 1 (hSPCA1) transports Ca2+ and Mn2+ into the Golgi lumen. Studies of the biological functions of hSPCA1 are limited by a lack of selective pharmacological tools for SPCA1 inhibition. The aim of this study was therefore to identify compounds that specifically inhibit hSPCA1 activity. We found that five 1,3-thiazole derivatives exhibited inhibitory action towards the ATP hydrolysis activity of hSPCA1a in a concentration-dependent manner. Among the derivatives tested, compound 1 was the most potent, completely inhibiting hSPCA1a activity with a half-maximal inhibition (IC50) value of 0.8 μM. Compound 1 also partially inhibited the activity of another Ca2+,Mn2+-ATPase (hSPCA2) and Ca2+-ATPase (rSERCA1a), but had no effect on Na+,K+-ATPase or H+,K+-ATPase. Treatment of HeLa cells with compound 1 led to fragmentation of the Golgi ribbon into smaller stacks. In addition, compound 1 mobilized intracellular Ca2+ in HeLa cells that had been pre-treated with thapsigargin. Therefore, based on its selectivity and potency, compound 1 may be a valuable tool with which to further explore the role of SPCA1 in cellular processes. •Five 1,3-thiazole derivatives show inhibitory potency toward hSPCA1a activity.•Compound 1 achieved complete inhibition of hSPCA1a with an IC50 value below 1 μM.•Compound 1 had no severe inhibitory effect on ion pump proteins analogous to hSPCA1a.•The morphology of the Golgi apparatus in HeLa cells was destroyed by compound 1.•Compound 1 mobilized intracellular Ca2+ from Thapsigargin-independent Ca2+ stores.