The Cardiac Ryanodine Receptor Provides a Suitable Pathway for the Rapid Transport of Zinc (Zn).

The sarcoplasmic reticulum (SR) in cardiac muscle is suggested to act as a dynamic storage for Zn release and reuptake, albeit it is primarily implicated in the Ca signaling required for the cardiac cycle. A large Ca release from the SR is mediated by the cardiac ryanodine receptor (RYR2), and while this has a prominent conductance for Ca in vivo, it also conducts other divalent cations in vitro. Since Zn and permeant Mg have similar physical properties, we tested if the RYR2 channel also conducts Zn. Using the method of planar lipid membranes, we evidenced that the RYR2 channel is permeable to Zn with a considerable conductance of 81.1 ± 2.4 pS, which was significantly lower than the values for Ca (127.5 ± 1.8 pS) and Mg (95.3 ± 1.4 pS), obtained under the same asymmetric conditions. Despite similar physical properties, the intrinsic Zn permeability (P/P = 2.65 ± 0.19) was found to be ~2.3-fold lower than that of Mg (P/P = 1.146 ± 0.071). Further, we assessed whether the channel itself could be a direct target of the Zn current, having the Zn finger extended into the cytosolic vestibular portion of the permeation pathway. We attempted to displace Zn from the RYR2 Zn finger to induce its structural defects, which are associated with RYR2 dysfunction. Zn chelators were added to the channel cytosolic side or strongly competing cadmium cations (Cd) were allowed to permeate the RYR2 channel. Only the Cd current was able to cause the decay of channel activity, presumably as a result of Zn to Cd replacement. Our findings suggest that the RYR2 channel can provide a suitable pathway for rapid Zn escape from the cardiac SR; thus, the channel may play a role in local and/or global Zn signaling in cardiomyocytes.