Document Type
Article
Publication Date
11-2017
Abstract
Although toxic when inhaled in high concentrations, the gas carbon monoxide (CO) is endogenously produced in mammals, and various beneficial effects are reported. For potential medicinal applications and studying the molecular processes underlying the pharmacological action of CO, so-called CO-releasing molecules (CORMs), such as tricabonyldichlororuthenium(II) dimer (CORM-2), have been developed and widely used. Yet, it is not readily discriminated whether an observed effect of a CORM is caused by the released CO gas, the CORM itself, or any of its intermediate or final breakdown products. Focusing on Ca2+- and voltage-dependent K+ channels (KCa1.1) and voltage-gated K+ channels (Kv1.5, Kv11.1) relevant for cardiac safety pharmacology, we demonstrate that, in most cases, the functional impacts of CORM-2 on these channels are not mediated by CO. Instead, when dissolved in aqueous solutions, CORM-2 has the propensity of forming Ru(CO)2 adducts, preferentially to histidine residues, as demonstrated with synthetic peptides using mass-spectrometry analysis. For KCa1.1 channels we show that H365 and H394 in the cytosolic gating ring structure are affected by CORM-2. For Kv11.1 channels (hERG1) the extracellularly accessible histidines H578 and H587 are CORM-2 targets. The strong CO-independent action of CORM-2 on Kv11.1 and Kv1.5 channels can be completely abolished when CORM-2 is applied in the presence of an excess of free histidine or human serum albumin; cysteine and methionine are further potential targets. Off-site effects similar to those reported here for CORM-2 are found for CORM-3, another ruthenium-based CORM, but are diminished when using iron-based CORM-S1 and absent for manganese-based CORM-EDE1.
Recommended Citation
Gessner, G., Sahoo, N., Swain, S. M., Hirth, G., Schönherr, R., Mede, R., Westerhausen, M., Brewitz, H. H., Heimer, P., Imhof, D., Hoshi, T., & Heinemann, S. H. (2017). CO-independent modification of K+ channels by tricarbonyldichlororuthenium(II) dimer (CORM-2). European journal of pharmacology, 815, 33–41. https://doi.org/10.1016/j.ejphar.2017.10.006
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Publication Title
European Journal of Pharmacology
DOI
10.1016/j.ejphar.2017.10.006
Comments
Original published version available at https://doi.org/10.1016/j.ejphar.2017.10.006