9-methyl-7-bromoeudistomin D, a powerful radio-labelable Ca++ releaser having caffeine-like properties, acts on Ca(++)-induced Ca++ release channels of sarcoplasmic reticulum.
9-Methyl-7-bromoeudistomin D (MBED), a derivative of eudistomin D isolated from a marine tunicate, induced Ca++ release from the heavy fraction of fragmented sarcoplasmic reticulum (HSR) in the same way as that of caffeine, followed by spontaneous Ca++ reuptake in the Ca++ electrode experiment. The rate of 45Ca++ efflux from HSR vesicles was accelerated markedly by MBED or caffeine in a concentration-dependent manner. The 50% effective concentrations of MBED and caffeine were approximately 1 microM and 1 mM, respectively, indicating that MBED is 1000 times more potent than caffeine in HSR. Procaine, ruthenium red or Mg++ caused concentration-dependent inhibition of MBED-triggered Ca++ release from HSR. The bell-shaped profile of Ca++ dependence for MBED is very similar to that of caffeine. The caffeine-produced maximum response of 45Ca++ efflux was increased further by adenosine-5'-(beta, gamma-methyl-ene)triphosphate, whereas that was not changed by MBED. MBED also caused Ca++ release from sarcoplasmic reticulum (SR) of chemically skinned fibers. These stimulatory effects of MBED on the Ca++ release from skeletal muscle SR were almost indistinguishable from those of caffeine except the difference in potencies. The [3H]ryanodine binding to junctional terminal cisternae membranes was not inhibited by MBED or caffeine. MBED did not cause Ca++ release from the light fraction of fragmented SR and turbidity change of mitochondrial suspension. These observations suggest a most likely idea that MBED binds to the caffeine-binding site in the Ca channel protein and thus produces the potentiation of Ca(++)-induced Ca++ release from SR.(ABSTRACT TRUNCATED AT 250 WORDS)
Seino
A
A
Mitsubishi Kasel Institute of Life Sciences, Tokyo, Japan.
Kobayashi
M
M
Kobayashi
J
J
Fang
Y I
YI
Ishibashi
M
M
Nakamura
H
H
Momose
K
K
Ohizumi
Y
Y
D000818:Animals; D001665:Binding Sites; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D002243:Carbolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D011343:Procaine / Q000494:pharmacology; D011817:Rabbits; D012430:Ruthenium Red / Q000494:pharmacology; D012433:Ryanodine / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D015220:Calcium Channels; D002243:Carbolines; D012430:Ruthenium Red; C060741:9-methyl-7-bromoeudistomin D; D012433:Ryanodine; D002110:Caffeine; D011343:Procaine; D008274:Magnesium; D002118:Calcium