Inhibition of Calcium-Dependent ATPase from Sarcoplasmic Reticulum by a New Class of Indolizidine Alkaloids, Pumiliotoxins A, B, and 251D |
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Authors: | R Tamburini E X Albuquerque J W Daly F C Kauffman |
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Institution: | Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.;Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland, U.S.A. |
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Abstract: | Abstract: Pumiliotoxins (PTX) A, B, and 251D, members of a new class of indolizidine alkaloids isolated from the skin of poison frogs of the family Dendrobatidae, inhibit Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from frog and rat hind-limb muscles. PTX-B and PTX-A appear to be relatively specific inhibitors of Ca2+-ATPase; PTX-A is much less potent than PTX-B. PTX-251D is a potent inhibitor of Ca2+-ATPase, and was also found to inhibit Na+, K+, and Mg2+-ATPases in rat brain synaptosomes. Caffeine and verapamil, two drugs known to affect calcium translocation, are very weak inhibitors of the Ca2+-ATPase. The K, values for inhibition of the Ca2+-ATPase of rat and frog sarcoplasmic reticulum by PTX-B were comparable and ranged between 22 and 36 μM. Inhibition of calcium-dependent ATPase in sarcoplasmic reticulum by pumiliotoxin-B is noncompetitive with calcium and is not readily reversible. Based on structure-activity profiles, it is concluded that inhibition of Ca2+-ATPase by the indolizidine alkaloids is responsible for the alkaloidelicited prolongation of twitch in intact muscle. |
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Keywords: | ATPase calcium dependent ATPase Na+-K+-Toxins-Pumiliotoxins-Skeletal muscle-Sarcoplasmic reticulum-Synaptosomes rat brain |
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