Nuclear localization of NCX: Role in Ca²⁺ handling and pathophysiological implications

Numerous lines of evidence indicate that nuclear calcium concentration ([Ca²⁺]_n) may be controlled independently from cytosolic events by a local machinery. In particular, the perinuclear space between the inner nuclear membrane (INM) and the outer nuclear membrane (ONM) of the nuclear envelope (NE) likely serves as an intracellular store for Ca²⁺ ions. Since ONM is contiguous with the endoplasmic reticulum (ER), the perinuclear space is adjacent to the lumen of ER thus allowing a direct exchange of ions and factors between the two organelles. Moreover, INM and ONM are fused at the nuclear pore complex (NPC), which provides the only direct passageway between the nucleoplasm and cytoplasm. However, due to the presence of ion channels, exchangers and transporters, it has been generally accepted that nuclear ion fluxes may occur across ONM and INM. Within the INM, the Na⁺/Ca²⁺ exchanger (NCX) isoform 1 seems to play an important role in handling Ca²⁺ through the different nuclear compartments. Particularly, nuclear NCX preferentially allows local Ca²⁺ flowing from nucleoplasm into NE lumen thanks to the Na⁺ gradient created by the juxtaposed Na⁺/K⁺-ATPase. Such transfer reduces abnormal elevation of [Ca²⁺]_n within the nucleoplasm thus modulating specific transductional pathways and providing a protective mechanism against cell death. Despite very few studies on this issue, here we discuss those making major contribution to the field, also addressing the pathophysiological implication of nuclear NCX malfunction.