Modulation of the Ca2+ channel voltage sensor and excitation-contraction coupling by silver.
Ag+ (0.5-10 microM) is known to produce a transient contraction of intact frog skeletal muscle fibers followed by complete inhibition of excitation-contraction (E-C) coupling. We have carried out physiological and biochemical experiments to investigate the basis of this effect. Dihydropyridine (DHP) Ca2+ channel blockers, which inhibit the voltage sensor of the Ca2+ channel, completely inhibit Ag+ contractions. Removal of extracellular Ca2+, or blockade of Ca2+ entry with cadmium, does not inhibit Ag+ contractions. Activation of the Ca2+ channel's voltage sensor with the Ca2+ channel agonists Bay K 8644 or with perchlorate, potentiates the Ag(+)-induced contraction. Ag+ binds to the partially purified rabbit skeletal muscle Ca2+ channel and inhibits DHP binding (IC50 = 1.1 microM) and sulfhydryl (SH) reactivity (IC50 = 0.11 microM) over the concentration range where it inhibits E-C coupling. Oxidation of free SH groups by H2O2 or their reaction with DTNB prevents Ag+ contractions, while DTT reduction of oxidized SH groups restores Ag+ contractions. These results suggest that Ag+ binds to critical SH groups on the DHP receptor Ca2+ channel, resulting in modification of the channel's voltage sensor and the failure of E-C coupling.
Oba
T
T
Department of Veterinary Anatomy and Cellular Biology, College of Veterinary Medicine, Ohio State University, Columbus 43210.
Yamaguchi
M
M
Wang
S
S
Johnson
J D
JD
D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004563:Electrochemistry; D015736:Felodipine / Q000494:pharmacology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D011892:Rana catesbeiana; D011896:Rana temporaria; D012834:Silver / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D015220:Calcium Channels; D013438:Sulfhydryl Compounds; D012834:Silver; D009543:Nifedipine; D015736:Felodipine