Journal
BIOCHEMICAL JOURNAL
Volume 366, Issue -, Pages 255-263Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20020431
Keywords
ATP regulation; immunosuppressant; phosphorylation; sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; (SERCA)
Categories
Ask authors/readers for more resources
The pharmacology of macrocyclic lactores is varied, with many beneficial effects in treating disease processes. FK-506, rapamycin and ascomycin have been utilized as immunosuppressant agents. Ivermectin is typically used to treat parasitic worm infections in mammals. Another immunosuppressant, cyclosporin A, is a cyclic oligotide that has similar immunosuppressant properties to those exerted by macrocyclic lactones. Here we report on the inhibition by these compounds of sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase (SERCA) Ca2+ pumps. Ivermectin, cyclosporin A and rapamycin all inhibited the skeletal muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA1). In addition, although ivermectin inhibited brain microsomal endoplasmic reticulum (type 2b) Ca2+-ATPase, cyclosporin A and rapamycin did not. As cyclosporin A also did not inhibit cardiac Ca2+-ATPase activity, this would suggest that it could be an isoform-specific inhibitor. Ivermectin was shown to be the most potent Ca2+-ATPase inhibitor of the macrocyclic lactones (IC50 = 7 muM). It appears to show a 'competitive' inhibition with respect to high concentrations of ATP by increasing the regulatory binding site K-m but without affecting the catalytic site K-m. In addition. ivermectin stabilizes the ATPase in an El conformational state, and inhibits Ca2+ release from the enzyme during turnover. This would suggest that ivermectin inhibits Ca2+ release from the luminal binding sites of the phosphoenzyme intermediate, a step that is known to be accelerated by high [ATP].
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available