Inhibition of large-conductance Ca2+-activated K+ channels by nanomolar concentrations of Ag+.
Silver has been widely used in various medical products because of its antibacterial properties. However, there is only limited information concerning silver-related cytotoxicity. In this study we show that Ag(+) at low nanomolar concentrations (<10 nM) strongly inhibits the activity of large-conductance Ca(2+)-activated K(+) channels (BK) (Slo1), a widely expressed and physiologically important potassium channel. The Ag(+) inhibition is caused by irreversible modification on cytosolically accessible parts of the BK channel. At least four intracellular cysteines are involved in this process. In addition, at least one of these key cysteines is not accessible to the bulkier thiolate-active reagent [2-(trimethylammonium)ethyl] methanethiosulfonate bromide. One of the cysteine-less constructs generated in this study shows gating properties similar to wild-type BK channel but with much lower Ag(+) sensitivity, in which the Ag(+) modification rate was decreased by approximately 20-fold. The results from the present study suggest a possible contribution of BK channel inhibition to the cytotoxicity of Ag(+) in humans and other species.
Zhou
Yu
Y
Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. zhouy@morpheus.wustl.edu
Xia
Xiaoming
X
Lingle
Christopher J
CJ
D000818:Animals; D002414:Cations, Monovalent; D003545:Cysteine / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005459:Fluorides / Q000633:toxicity*; D066298:In Vitro Techniques; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D018030:Silver Compounds / Q000633:toxicity*; D012835:Silver Nitrate / Q000633:toxicity; D014982:Xenopus laevis
D002414:Cations, Monovalent; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D018030:Silver Compounds; C105022:silver fluoride; D012835:Silver Nitrate; D003545:Cysteine; D005459:Fluorides