The Cardiac Ryanodine Receptor Provides a Suitable Pathway for the Rapid Transport of Zinc (Zn²⁺)

The sarcoplasmic reticulum (SR) in cardiac muscle is suggested to act as a dynamic storage for Zn²⁺ release and reuptake, albeit it is primarily implicated in the Ca²⁺ signaling required for the cardiac cycle. A large Ca²⁺ release from the SR is mediated by the cardiac ryanodine receptor (RYR2), and while this has a prominent conductance for Ca²⁺ in vivo, it also conducts other divalent cations in vitro. Since Zn²⁺ and permeant Mg²⁺ have similar physical properties, we tested if the RYR2 channel also conducts Zn²⁺. Using the method of planar lipid membranes, we evidenced that the RYR2 channel is permeable to Zn²⁺ with a considerable conductance of 81.1 ± 2.4 pS, which was significantly lower than the values for Ca²⁺ (127.5 ± 1.8 pS) and Mg²⁺ (95.3 ± 1.4 pS), obtained under the same asymmetric conditions. Despite similar physical properties, the intrinsic Zn²⁺ permeability (P_Ca/P_Zn = 2.65 ± 0.19) was found to be ~2.3-fold lower than that of Mg²⁺ (P_Ca/P_Mg = 1.146 ± 0.071). Further, we assessed whether the channel itself could be a direct target of the Zn²⁺ current, having the Zn²⁺ finger extended into the cytosolic vestibular portion of the permeation pathway. We attempted to displace Zn²⁺ from the RYR2 Zn²⁺ finger to induce its structural defects, which are associated with RYR2 dysfunction. Zn²⁺ chelators were added to the channel cytosolic side or strongly competing cadmium cations (Cd²⁺) were allowed to permeate the RYR2 channel. Only the Cd²⁺ current was able to cause the decay of channel activity, presumably as a result of Zn²⁺ to Cd²⁺ replacement. Our findings suggest that the RYR2 channel can provide a suitable pathway for rapid Zn²⁺ escape from the cardiac SR; thus, the channel may play a role in local and/or global Zn²⁺ signaling in cardiomyocytes.