# Golgi Metal Ion Homeostasis in Human Health and Diseases
## 2 Ca\({}^{2+}\)/Mn\({}^{2+}\) Transporters and Channels
### Ca\({}^{2+}\)/Mn\({}^{2+}\) Transporters in the Golgi  
The early Golgi compartments host many Ca\({}^{2+}\) pumps that are also highly abundant in the ER, such as Sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCAs), possibly because of the constant content exchange between the Golgi and ER, mediated by direct contact and vesicles [28; 29]. On the other hand, the Golgi also contains unique Ca\({}^{2+}\) transporters not found in the ER, including Secretory pathway Ca\({}^{2+}\)-transporting ATPases (SPCAs, also known as the Calcium-transporting ATPase type 2C members) and TMEM165 [29]. Different from ER Ca\({}^{2+}\) pumps, they usually show high affinity to Mn\({}^{2+}\) ion and therefore act as Mn\({}^{2+}\) transporters as well. The human genome has three SERCA genes, ATP2A1, ATP2A2, and ATP2A3, which encode P2A ATPase family members SERCA1 (SERCA 1a, 1b), 2 (SERCA 2a, 2b), and 3 (SERCA 3 a-e), respectively. The major structure of SERCA contains a membrane (M) domain consisting of 10 transmembrane helices containing the ion-binding sites, and a large cytosolic domain including the actuator (A), phosphorylation (P), and nucleotide-binding (N) domains. A highly conserved sequence DKTGTLT in the P-domain is found in all P-type ATPase family members and catalyzes the autophosphorylation of the P-domain [30]. The transport of Ca\({}^{2+}\) from the cytosol into the Golgi lumen by these P-type ATPases is facilitated by the ATP-hydrolysis-dependent conformational change between the two major statuses (E1 and E2) of the SERCA enzymes. The E1 status presents high Ca\({}^{2+}\)-binding affinity and exposure of the two Ca\({}^{2+}\)-binding sites to the cytosol [31]. The binding of Ca\({}^{2+}\) and ATP causes phosphorylation on a highly conserved aspartate, leading to a conformational change to the E2 status, which shows lower affinity to the Ca\({}^{2+}\) and reorients toward the lumenal face. Release of Ca\({}^{2+}\) and ATP hydrolysis are accompanied by the dephosphorylation that leads to the conformational change back to the E1 state, which represents the end of a Ca\({}^{2+}\) transport cycle [32]. In human cells, two different genes, ATP2C1 and ATP2C2, encode four SPCA1 splice variants and SPCA2, respectively [33; 34]. Similar to SERCAs and other P-type ATPases, SPCA isoforms undergoes Ca\({}^{2+}\) (or Mn\({}^{2+}\))-binding-induced autophosphorylation of the conserved asparagine (Asp350 in human SPCA1 and Asp351 in SERCA1a) [35]. The reversible SPCA cycle transferring ion across the membrane is also facilitated by the conformational change between the E1 and E2 statuses with different affinity to the ion and orientation [36]. Different from SERCAs that transport two Ca\({}^{2+}\) ions upon the hydrolysis of one ATP, the SPCA pumps contain only one Ca\({}^{2+}\)-binding site, therefore, transport only one Ca\({}^{2+}\) ion into the Golgi lumen per ATP. Besides, the maximal turnover rates of the SPCA ATPase are much lower than that of SERCA1a [37]. Another unique characteristic in contrast to most other Ca\({}^{2+}\)-ATPases is that SPCAs display high affinity toward Mn\({}^{2+}\) and thus also act as Mn\({}^{2+}\) transporters. Since only one ion-binding site is conserved in SPCAs, it is suggested that only one Ca\({}^{2+}\) or Mn\({}^{2+}\) is transported by the energy derived from the hydrolysis of one ATP molecule. Although both SPCA isoforms catalyze Ca\({}^{2+}\) or Mn\({}^{2+}\)-dependent autophosphorylation, SPCA1 shows a lower Ca\({}^{2+}\) affinity and slightly lower Mn\({}^{2+}\) affinity comparing with SPCA2 [35]. It is widely accepted that SERCAs and SPCAs both contribute to the Ca\({}^{2+}\) uptake into the Golgi since it is only partially inhibited by the SERCA inhibitor thapsigargin [38; 39]. Isolated membranes show enrichment of SERCA in the ER and _cis_-Golgi while SPCA1 in the _trans_-Golgi membranes [40]. This conclusion was supported by immunoelectron microscopy (immuno-EM) [41].