Inhibition of calcium-dependent ATPase from sarcoplasmic reticulum by a new class of indolizidine alkaloids, pumiliotoxins A, B, and 251D.
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 Ki values for inhibition of the Ca2+-ATPase of rat and frog sarcoplasmic reticulum by PTX-B were comparable and ranged between 22 and 36 microM. 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 alkaloid-elicited prolongation of twitch in intact muscle.
D000470:Alkaloids / Q000494:pharmacology*; D000664:Amphibian Venoms / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D007212:Indolizines; D007700:Kinetics; D009132:Muscles / Q000201:enzymology; D010880:Piperidines; D011894:Rana pipiens; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology
D000470:Alkaloids; D000664:Amphibian Venoms; D007212:Indolizines; D010880:Piperidines; D002110:Caffeine; C031598:pumiliotoxin B; D014700:Verapamil; D000252:Calcium-Transporting ATPases