Abstract
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 (PCa/PZn = 2.65 ± 0.19) was found to be ~2.3-fold lower than that of Mg2+ (PCa/PMg = 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.
Highlights
Zinc (Zn2+) is one of the most abundant metal cations in mammalian cells, with diverse functions in numerous physiological processes important for differentiation, growth and survival
Our results indicate that the RYR2 channel may play a role in Zn2+ signaling in cardiomyocytes, and the channel itself could be a direct target for the localized Zn2+ increase, with the Zn2+ finger, a well-known Zn2+-binding site, extending into the cytosolic vestibular portion of the RYR2 permeation pathway [55]
A potential role of the RYR2 Zn2+ current in local Zn2+ signaling was assessed by computing Zn2+ accumulation near potential molecular targets, such as neighboring RYR2 channels and the Zn2+ finger domain extending into the cytosolic vestibular portion of the RYR2 permeation pathway [55]
Summary
Zinc (Zn2+) is one of the most abundant metal cations in mammalian cells, with diverse functions in numerous physiological processes important for differentiation, growth and survival (reviewed in [1,2]). Deficiency and excess have been documented in a wide range of pathological conditions, including cancer, diabetes and inflammatory, cardiovascular and neurodegenerative diseases, which have been the topic of several review articles [3–9]. While catalytic and structural functions of Zn2+ are well-established in a great number of metalloproteins [10,11], Zn2+. Ca2+, free intracellular Zn2+ concentration is tightly controlled and fluctuates in an extraordinarily narrow range (pM–nM), depending on the cell type [12–15]. In addition to cytosolic Zn2+-chelating proteins (reviewed in [16]), various Zn2+ transporters (carriertype) are involved in controlling intracellular Zn2+, such as ZnT proteins exporting Zn2+
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