The Role of the Golgi-Resident SPCA Ca2+/Mn2+ Pump in Ionic Homeostasis and Neural Function

Abstract

Recent evidence highlights the functional importance of the Golgi apparatus (GA) in neurological diseases. The functions of the mammalian GA, in addition to the processing and transport of cargo, also include ionic homeostasis. Besides Ca²⁺-release channels which serves GA as an agonist-sensitive intracellular Ca²⁺ store, and Ca²⁺-binding proteins, the GA contains Ca²⁺-uptake mechanisms consisting of the well-known sarco-endoplasmic reticulum Ca²⁺-transport ATPases and the much less characterized secretory-pathway Ca²⁺-transport ATPases (SPCA). SPCA can transport both Ca²⁺ and Mn²⁺ into the Golgi lumen and therefore is involved in the cytosolic and intra-Golgi Ca²⁺ and Mn²⁺ homeostasis. It has shown that both of the mRNA and protein of SPCAs are highly expressed in brain. In addition, brain is the region with the highest activity of SPCA isoforms, which may be related to the involvement of Ca²⁺ and Mn²⁺ homeostasis in neural functions. In this review, we compile some recent findings showing that the SPCA isoform plays a much more important role in intracellular ionic homeostasis than previously anticipated and illustrating the involvement of SPCA isoforms in certain neurophysiological or neuropathological process. We are interested in gaining insight into the intricate role of the SPCA pumps to explain the GA-specific functions in neurological disorders.

Manganese-induced turnover of TMEM165

“…Current knowledge supports that this supply is realized via the action of SPCA1 (secretory pathway Ca-ATPase 1: ATP2C1) and SPCA2 (ATP2C2). SPCA1 is ubiquitously expressed and mediates the import of Ca2+/Mn2+ into the Golgi lumen (11, 12). The tissue expression of SPCA2 is more restricted.…”

“…The tissue expression of SPCA2 is more restricted. However the importance of the dual transport function in cellular processes is not yet completely deciphered (12). Overexpression of SPCA1 has been shown to facilitate Mn2+ accumulation into the Golgi (13) and it was thus proposed that SPCA1 was a way to detoxify cytosolic Mn2+ accumulation by sequestering it into the secretory pathway.…”

Manganese Transport Across the Pulmonary Epithelium

“…A second transporter, the SPCA Ca 12 /Mn 12 pump, has been shown to play a role in uptake of manganese by the Golgi apparatus, serving to limit intracellular damage due to toxic levels of intracellular manganese. 120 Overexpression of SPCA in vitro protects against manganese toxicity, 121 thus this factor should also be examined as a potential metal handling player by the pulmonary epithelium. Finally, emerging evidence that the ATP12A2 (PARK9) plays a role in manganese toxicity 122 further suggests this P-type ATPase possibly interacts in lung metal homeostasis.…”

The Golgi Apparatus: Panel Point of Cytosolic Ca2+Regulation

“…data]. Neural functions associated with GA Ca 2+ regulation, especially by SPCAs, were reviewed in our previous paper [118]. …”