The role of Zn2+ in shaping intracellular Ca2+ dynamics in the heart

Abstract

Increasing evidence suggests that Zn2+ acts as a second messenger capable of transducing extracellular stimuli into intracellular signaling events. The importance of Zn2+ as a signaling molecule in cardiovascular functioning is gaining traction. In the heart, Zn2+ plays important roles in excitation-contraction (EC) coupling, excitation-transcription coupling, and cardiac ventricular morphogenesis. Zn2+ homeostasis in cardiac tissue is tightly regulated through the action of a combination of transporters, buffers, and sensors. Zn2+ mishandling is a common feature of various cardiovascular diseases. However, the precise mechanisms controlling the intracellular distribution of Zn2+ and its variations during normal cardiac function and during pathological conditions are not fully understood. In this review, we consider the major pathways by which the concentration of intracellular Zn2+ is regulated in the heart, the role of Zn2+ in EC coupling, and discuss how Zn2+ dyshomeostasis resulting from altered expression levels and efficacy of Zn2+ regulatory proteins are key drivers in the progression of cardiac dysfunction.

Figure 1.

Zn²⁺ transporters in the heart. (A) Localization of zinc transporters in the heart. ZIP transporters are illustrated in blue on the left of the image while ZnT transporters are colored in red on the right of the image. Transporters with confirmed protein expression through the Human Protein Atlas or reported in published Western blot/immunofluorescent in heart tissue homogenates, isolated cardiomyocytes, or cardiac cell lines (such as H9C2 cells) were included. rER, rough ER; TGN, trans-Golgi network. Created with BioRender.com. (B) RNA expression of Zn²⁺ transporters in normalized protein-coding transcripts per million (nTPM) in human heart. Figure was created using information available from the Human Protein Atlas (2022), Uhlén et al. (2015), and Choi et al. (2018).

Figure 2.

RNA expression of S/ER-located Zn²⁺ transporters. (A) Mean reads per kilobase of transcript per million reads mapped (RPKM) of Zn²⁺ transporters in human heart (RNA sequencing [RNA-Seq] data from Fagerberg et al., 2014). (B) Mean RPKM of Zn²⁺ transporters in rat heart (21 wk; RNA-Seq data from Yu et al., 2014). (C) Mean RPKM of Zn²⁺ transporters in mouse heart (RNA-Seq data from Yue et al., 2014).

Figure 3.

Possible Zn²⁺ binding sites on MG23. Partial sequence alignment of human zinc transporters ZIP1, ZIP2, and ZIP3 illustrating the conserved Zn²⁺ binding motif, H-x-x-x-E. Histidine residues (H) are highlighted in orange and glutamate (E) residues are highlighted in blue. This motif is also conserved across human (h), rat (r), and murine (m) MG23.

Figure 4.

Graphical summary of the suggested role of MG23 in cardiovascular function. MG23 may contribute to the release of Ca²⁺ from S/ER Ca²⁺ stores. In pathophysiological conditions where intracellular Zn²⁺ is elevated, the activity of MG23 will be increased, leading to increased release of Ca²⁺ from the S/ER. Increased [Zn²⁺]_i will result in activation of RyR2. Dotted lines and question marks suggest putative interactions/functions. Figure created with BioRender.com.