Abstract
Plasma membrane calcium ATPases (PMCA) are key proteins in the maintenance of calcium (Ca2+) homeostasis. Dysregulation of PMCA function is associated with several human pathologies, including neurodegenerative diseases, and, therefore, these proteins are potential drug targets to counteract those diseases. Gold compounds, namely of Au(I), are well-known for their therapeutic use in rheumatoid arthritis and other diseases for centuries. Herein, we report the ability of dichloro(2-pyridinecarboxylate)gold(III) (1), chlorotrimethylphosphinegold(I) (2), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I) chloride (3), and chlorotriphenylphosphinegold(I) (4) compounds to interfere with the Ca2+-ATPase activity of pig brain purified PMCA and with membranes from SH-SY5Y neuroblastoma cell cultures. The Au(III) compound (1) inhibits PMCA activity with the IC50 value of 4.9 µM, while Au(I) compounds (2, 3, and 4) inhibit the protein activity with IC50 values of 2.8, 21, and 0.9 µM, respectively. Regarding the native substrate MgATP, gold compounds 1 and 4 showed a non-competitive type of inhibition, whereas compounds 2 and 3 showed a mixed type of inhibition. All gold complexes showed cytotoxic effects on human neuroblastoma SH-SY5Y cells, although compounds 1 and 3 were more cytotoxic than compounds 2 and 4. In summary, this work shows that both Au (I and III) compounds are high-affinity inhibitors of the Ca2+-ATPase activity in purified PMCA fractions and in membranes from SH-SY5Y human neuroblastoma cells. Additionally, they exert strong cytotoxic effects.
Highlights
Calcium ion (Ca2+) is an essential element in the functioning of several intracellular processes
The present study shows that Plasma membrane calcium ATPases (PMCA) activity is inhibited by both Au(I) or Au(III) compounds
Significant inhibition values were found for the Au(I) compound 4 (IC50 < 1 μM), like those previously described for SERCA
Summary
Calcium ion (Ca2+) is an essential element in the functioning of several intracellular processes. The P-ATPases are characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle and can be specific carriers of other ions, such as H+, Na+, K+, Mg2+, Ag+ and Ag2+, Zn2+, Co2+, Pb2+, Ni2+, and Cu2+, as well as contaminant ion metals, such as Cd2+ and Hg2+ [5] These ATPases have fundamental roles in the regulation of all those ions and/or detoxification in the case of contaminating metals. Regarding Ca2+, there are three types of Ca2+-ATPases involved in Ca2+ homeostasis: the plasma membrane Ca2+-ATPase (PMCA), which pumps the excess of Ca2+ out of the cell, and two intracellular pumps that accumulate Ca2+ into the sarco/endoplasmic reticulum (SERCA) and to the secretory pathway (SPCA), respectively. The three types of pumps are encoded by separate genes, giving rise to four major PMCA isoforms, three SERCA isoforms, and two SPCA isoforms [6,7,8]
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