Heavy metals induce rapid calcium release from sarcoplasmic reticulum vesicles isolated from skeletal muscle.

Abstract

Micromolar concentrations of mercury, silver, and other reagents known to react with sulfhydryl groups are shown to stimulate ATPase activity and inhibit active calcium uptake in sarcoplasmic reticulum vesicles derived from rabbit fast skeletal muscle. These effects are caused by a dramatic increase in the calcium permeability of the sarcoplasmic reticulum. Measurements of Ca2+ permeability were made using both isotopes and by spectrophotometric techniques using the Ca2+ indicator arsenazo HI. Air oxidation of a sulfhydryl group to a disulfide group also leads to-a large increase in the calcium permeability of the sarcoplasmic reticulum. 1526The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Multiple Classes of Sulfhydryls Modulate the Skeletal Muscle Ca2+ Release Channel

“…N-Ethylmaleimide (NEM), 1 a sulfhydryl alkylating agent, activates Ca 2ϩ release at low concentrations, while it inhibits release at higher concentrations (27). 2 NEM, however, induces Ca 2ϩ release with a slower onset than the heavy metals, a finding that has been interpreted to mean that the sulfhydryls responsible for the observed effects on Ca 2ϩ release are in a hydrophilic environment (9). Quinn and Ehrlich (28) reported that modification of cysteines on the Ca 2ϩ release channel by methiosulfonate compounds reduces the conductance of the channel.…”

“…These studies led Abramson and Salama (10) to propose a model for redox modulation of the channel that involves three different sulfhydryl groups that exist in close proximity and that can form mixed disulfides to open or close the channel. The evidence that the channel can be altered by oxidation is conclusive (3)(4)(5)(6)(7)(8)(9)(10)(11); the question is whether this oxidation plays a physiological role in skeletal muscle. It is not yet known if disulfide interchange or oxidation-reduction of sulfhydryls on the Ca 2ϩ release channel contribute to normal excitation-contraction coupling, but an increasing body of evidence suggests that such a mechanism could be an important modulatory element.…”

“…Oxidizing agents that stimulate Ca 2ϩ release from the sarcoplasmic reticulum include H 2 O 2 (3), 2,2Ј-dithiodipyridine, 4,4Ј-dithiodipyridine (4), Cu 2ϩ phthalocyanine dyes (5), anthraquinone doxorubicin (6,7), and thimerosal (8). Heavy metals such as Hg 2ϩ , Ag ϩ , Cu 2ϩ , Cd 2ϩ , and Zn 2ϩ have also been reported to induce Ca 2ϩ release, either by directly interacting with a sulfhydryl or by causing oxidation (9). These studies led Abramson and Salama (10) to propose a model for redox modulation of the channel that involves three different sulfhydryl groups that exist in close proximity and that can form mixed disulfides to open or close the channel.…”

“…The channel opens in response to a signal from the transverse tubules, which is triggered by membrane depolarization (2), and the resulting flux of Ca 2ϩ from the sarcoplasmic reticulum initiates the sequence of events that leads to muscle contraction. Several laboratories have clearly demonstrated that the activity of the Ca 2ϩ release channel is modulated by oxidation-reduction reactions (3)(4)(5)(6)(7)(8)(9)(10)(11). Oxidizing agents that stimulate Ca 2ϩ release from the sarcoplasmic reticulum include H 2 O 2 (3), 2,2Ј-dithiodipyridine, 4,4Ј-dithiodipyridine (4), Cu 2ϩ phthalocyanine dyes (5), anthraquinone doxorubicin (6,7), and thimerosal (8).…”

Biphasic modulation of ryanodine binding to sarcoplasmic reticulum vesicles of skeletal muscle by Zn2+ ions

“…It has been reported that, similarly to some heavy metals such as Cu# + , Hg# + and Cd# + , Zn# + can induce Ca# + release from sarcoplasmic reticulum (SR) vesicles of skeletal muscle [8], suggesting an effect of Zn# + on RyR1s. However, we observed recently (X. Y. Cheng, K. Y. Chen, X. H. Zhang and P. H. Zhu, unpublished work) that the contraction induced by 5 mM caffeine was depressed in small bundles of rat soleus muscles perfused with saline containing 20 µM [Zn# + ] f .…”