The pharmacology of macrocyclic lactones 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 = 7μM). It appears to show a ‘competitive’ inhibition with respect to high concentrations of ATP by increasing the regulatory binding site Km but without affecting the catalytic site Km. In addition, ivermectin stabilizes the ATPase in an E1 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].
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August 2002
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Research Article|
August 15 2002
The inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by macrocyclic lactones and cyclosporin A
Jonathan G. BILMEN;
Jonathan G. BILMEN
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Laura L. WOOTTON;
Laura L. WOOTTON
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Francesco MICHELANGELI
Francesco MICHELANGELI
1
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
1To whom correspondence should be addressed (e-mail F.Michelangeli@bham.ac.uk).
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Publisher: Portland Press Ltd
Received:
March 18 2002
Revision Received:
May 09 2002
Accepted:
May 22 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 255–263.
Article history
Received:
March 18 2002
Revision Received:
May 09 2002
Accepted:
May 22 2002
Citation
Jonathan G. BILMEN, Laura L. WOOTTON, Francesco MICHELANGELI; The inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by macrocyclic lactones and cyclosporin A. Biochem J 15 August 2002; 366 (1): 255–263. doi: https://doi.org/10.1042/bj20020431
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