# Golgi Metal Ion Homeostasis in Human Health and Diseases
## 2 Ca\({}^{2+}\)/Mn\({}^{2+}\) Transporters and Channels
### Ca\({}^{2+}\)-Binding Proteins in the Golgi Lumen  
In addition to the Ca\({}^{2+}\) transporters and release channels summarized above, Ca\({}^{2+}\)-binding proteins are another factor involved in Ca\({}^{2+}\) homeostasis in the Golgi lumen. CALNUC, 45 kDa calcium-binding protein (Cab45), p54/NEFA, and calumenin are identified as major Ca\({}^{2+}\) binding proteins found specifically in the Golgi lumen. CALNUC (also known as Nucleobindin-1), an EF-hand, Ca\({}^{2+}\)-binding peripheral membrane protein closely linked with the lumenal surface of the _cis_-Golgi cisternae, is the most abundant and well-characterized Golgi Ca\({}^{2+}\) binding protein [53]. Transiently expressed CALNUC co-distributes with IP3R1 in cells, which increases Ca\({}^{2+}\) storage as well as Ca\({}^{2+}\) release upon ATP or IP3 stimulation [47]. Overexpression of SPCA upregulates the expression of CALNUC, indicating that CALNUC, together with SERCA and IP3R, is involved in establishment of the agonist-mobilizable Golgi Ca\({}^{2+}\) store.  
Cab45 is the first ubiquitous Golgi Ca\({}^{2+}\)-binding protein identified. It is a soluble Golgi lumen-resident protein that binds Ca\({}^{2+}\) via its EF-hands [54]. Retention of Cab45 in the TGN is Ca\({}^{2+}\)-dependent, which is disrupted by treatment of cells with a Ca\({}^{2+}\) ionophore [55], and is regulated by the Golgi resident serine/threonine kinase Fam20C [56]. Once bound to Ca\({}^{2+}\), Cab45 oligomerizes and is recruited by secretory proteins. Via super resolution microscopy, the Cab45 oligomer-cargo complex is detected to be preferentially colocalized with the TGN Ca\({}^{2+}\) pump SPCA1. Phosphorylation of Cab45 by Fam20C reduces the size of Cab45 oligomers, abolishes the TGN retention, and enhances the sorting and secretion of Cab45-cargo complex [56]. These results suggest the possibility that a functional sorting complex formed by Cab45, SPCA1, and cargo protein is regulated by Golgi Ca\({}^{2+}\)[57].  
p54/NEFA [58] and calumenin are two other Ca\({}^{2+}\)-binding proteins found in the Golgi lumen. p54/NEFA is a medial Golgi membrane-associated lumenal protein sharing sequence homology with CALNUC [59]. Calumenin is a glycosylated secretory protein distributed throughout the secretory pathway with a low affinity to Ca\({}^{2+}\) ions [60; 61]. It is reported to interact with RyR2 and SERCA in cardiac and skeletal sarcoplasmic reticulum, and therefore suggested to be a regulator of RyR2 and SERCA, which is tightly coupled with Ca\({}^{2+}\) cycling [62; 63; 64].  
In summary, the Golgi is equipped with all the molecular components necessary for maintaining Ca\({}^{2+}\) homeostasis in the Golgi lumen: Ca\({}^{2+}\) ATPases that pump Ca\({}^{2+}\) into the Golgi lumen, Ca\({}^{2+}\) channels that release Ca\({}^{2+}\) into the cytoplasm, and Ca\({}^{2+}\)-binding proteins that buffer Ca\({}^{2+}\) in the Golgi lumen. With all these regulators in action, the distinct sub-compartments of the Golgi appear to have a decreasing lumen Ca\({}^{2+}\) concentration through heterogenous expression of Ca\({}^{2+}\) transporters and channels: the _cis_-Golgi expresses mainly SERCA and IP3 Rs and contains around 250 \(\upmu\)M lumenal Ca\({}^{2+}\); the medial Golgi mainly expresses SERCA and SPCA1; and the _trans_-Golgi mainly expresses SPCA1 and RyRs, with a lumenal Ca\({}^{2+}\) of about 130 \(\upmu\)M (Figure 1) [29].  
Figure 1: Ca\({}^{2+}\) concentration and Ca\({}^{2+}\) homeostasis-related molecules in different Golgi sub-compartments. The _cis_-Golgi expresses mainly SERCA and IP3 Rs and contains around 250 \(\upmu\)M lumenal Ca\({}^{2+}\); the medial Golgi mainly expresses SERCA and SPCA1; and the _trans_-Golgi mainly expresses SPCA1 and RyRs, with a lumenal Ca\({}^{2+}\) of about 130 \(\upmu\)M.