Glycosylation controls sodium-calcium exchanger 3 sub-cellular localization during cell cycle

Abstract

The Na/Ca exchanger (NCX) is a membrane antiporter that has been identified in the plasma membrane, the inner membrane of the nuclear envelope and in the membrane of the endoplasmic reticulum (ER). In humans, three genes have been identified, encoding unique NCX proteins. Although extensively studied, the NCX's sub-cellular localization and mechanisms regulating the activity of different subtypes are still ambiguous. Here we investigated the subcellular localization of the NCX subtype 3 (NCX3) and its impact on the cell cycle. Two phenotypes, switching from one to the other during the cell cycle, were detected. One phenotype was NCX3 in the plasma membrane during S and M phase, and the other was NCX3 in the ER membrane during resting and interphase. Glycosylation of NCX3 at the N45 site was required for targeting the protein to the plasma membrane, and the N45 site functioned as an on-off switch for the translocation of NCX3 to either the plasma membrane or the membrane of the ER. Introduction of an N-glycosylation deficient NCX3 mutant led to an arrest of cells in the G0/G1 phase of the cell cycle. This was accompanied by accumulation of de-glycosylated NCX3 in the cytosol (that is in the ER), where it transported calcium ions (Ca) from the cytosol to the ER. These results, obtained in transfected HEK293T and HeLa and confirmed endogenously in SH-SY5Y cells, suggest that cells can use a dynamic Ca signaling toolkit in which the NCX3 sub-cellular localization changes in synchrony with the cell cycle.

Disturbance of calcium homeostasis and myogenesis caused by TET2 deletion in muscle stem cells

“…Furthermore, the Slc8a3 displayed a tissue-specific distribution pattern in vivo and in muscle tissue, its expression fluctuates at different developmental stages [ 58 , 59 ]. Previous studies also showed that the intranuclear localization of Slc8a3 is associated with the cell cycle and that the inhibition of NCX proteins impairs the proliferation of myofibroblasts [ 60 – 62 ]. According to a knockout mouse model, Slc8a3 deletion caused dysregulation of muscle calcium homeostasis and myofiber necrosis [ 34 ].…”

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

“…The glycosylation of receptor molecules will change their stability, solubility, and regional localization in cells, and this will play an important role in regulating the cell cycle, signal transduction, protein expression regulation, responses, and clearing of foreign matter in cells [34,35]. Vast evidence supports the view that the glycation of proteins is one of the main factors contributing to aging and is an important element of the etiopathology of age-related diseases, especially type 2 diabetes mellitus, hypertension, and neurodegenerative diseases [36,37,38].…”

β-N-methylamino-L-alanine (BMAA) suppresses cell cycle progression of non-neuronal cells

“…A recent study reported that an injection of a sub-toxic dose of BMAA into the cerebrospinal fluid delayed the progression of ALS in an ALS mouse model, which was suggested to have occurred due to prevention of the down-regulation of Na + /Ca 2+ exchanger 3 (NCX3) 42 . NCX3 has been reported to be involved in cell cycle progression 43 . The subcellular localization of NCX3 changes during the cell cycle: NCX3 is detected in the plasma membrane during the S or M phases, but is mainly observed in the ER membrane in the G0/G1 phase.…”