The Cardiac Ryanodine Receptor Provides a Suitable Pathway for the Rapid Transport of Zinc (Zn(2+))

The sarcoplasmic reticulum (SR) in cardiac muscle is suggested to act as a dynamic storage for Zn(2+) release and reuptake, albeit it is primarily implicated in the Ca(2+) signaling required for the cardiac cycle. A large Ca(2+) release from the SR is mediated by the cardiac ryanodine receptor (RYR2), and while this has a prominent conductance for Ca(2+) in vivo, it also conducts other divalent cations in vitro. Since Zn(2+) and permeant Mg(2+) have similar physical properties, we tested if the RYR2 channel also conducts Zn(2+). Using the method of planar lipid membranes, we evidenced that the RYR2 channel is permeable to Zn(2+) with a considerable conductance of 81.1 ± 2.4 pS, which was significantly lower than the values for Ca(2+) (127.5 ± 1.8 pS) and Mg(2+) (95.3 ± 1.4 pS), obtained under the same asymmetric conditions. Despite similar physical properties, the intrinsic Zn(2+) permeability (P(Ca)/P(Zn) = 2.65 ± 0.19) was found to be ~2.3-fold lower than that of Mg(2+) (P(Ca)/P(Mg) = 1.146 ± 0.071). Further, we assessed whether the channel itself could be a direct target of the Zn(2+) current, having the Zn(2+) finger extended into the cytosolic vestibular portion of the permeation pathway. We attempted to displace Zn(2+) from the RYR2 Zn(2+) finger to induce its structural defects, which are associated with RYR2 dysfunction. Zn(2+) chelators were added to the channel cytosolic side or strongly competing cadmium cations (Cd(2+)) were allowed to permeate the RYR2 channel. Only the Cd(2+) current was able to cause the decay of channel activity, presumably as a result of Zn(2+) to Cd(2+) replacement. Our findings suggest that the RYR2 channel can provide a suitable pathway for rapid Zn(2+) escape from the cardiac SR; thus, the channel may play a role in local and/or global Zn(2+) signaling in cardiomyocytes.