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Inhibition of Calcium‐Dependent ATPase from Sarcoplasmic Reticulum by a New Class of Indolizidine Alkaloids, Pumiliotoxins A, B, and 251D
Author(s) -
Tamburini R.,
Albuquerque E. X.,
Daly J. W.,
Kauffman F. C.
Publication year - 1982
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1982.tb12554.x
Subject(s) - endoplasmic reticulum , calcium , atpase , verapamil , indolizidine , alkaloid , calcium atpase , biochemistry , chemistry , biology , stereochemistry , enzyme , organic chemistry
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 Ca 2+ ‐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 Ca 2+ ‐ATPase; PTX‐A is much less potent than PTX‐B. PTX‐251D is a potent inhibitor of Ca 2+ ‐ATPase, and was also found to inhibit Na + , K + , and Mg 2+ ‐ATPases in rat brain synaptosomes. Caffeine and verapamil, two drugs known to affect calcium translocation, are very weak inhibitors of the Ca 2+ ‐ATPase. The K, values for inhibition of the Ca 2+ ‐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 Ca 2+ ‐ATPase by the indolizidine alkaloids is responsible for the alkaloidelicited prolongation of twitch in intact muscle.