Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Abstract

The mammalian nuclear pore complex is comprised of ∼ 30 different nucleoporins (Nups). It governs the nuclear import of gene expression modulators and the export of mRNAs. In cardiomyocytes, Na(+)-H(+) exchanger-1 (NHE1) is an integral membrane protein that exclusively regulates intracellular pH (pHi) by exchanging one intracellular H(+) for one extracellular Na(+). However, the role of Nups in cardiac NHE1 expression remains unknown. We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA. The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5'-UTR (-412 to -213 nt) of nhe1 mRNA. Nup35 ablation weakens the resistance of cardiomyocytes to an acid challenge by depressing NHE1 expression. Moreover, we identify that Nup35 and NHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro. Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification. We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression. This finding reveals a novel regulatory mechanism of cardiomyocyte pHi, and may provide insight into the therapeutic strategy for ischemic cardiac diseases.

Nucleoporin 107 facilitates the nuclear export of Scn5a mRNA to regulate cardiac bioelectricity

“…Till now we do not know the detail of this posttranscriptional regulation, but it seems that the three‐dimensional shape of Scn5a mRNA is formed before its entry into the cytoplasm. Interestingly, the 5′‐UTR, which is demonstrated to be a crucial part, guiding the mRNA through the nuclear pore, has no interaction with Nup107, whereas the CDS and 3′‐UTR of Scn5a mRNA are all involved in the contact with Nup107 (Figure D). No defined region was identified to be responsible for Scn5a mRNA export.…”

“…There is evidence showing that the biallelic NUP107 mutations cause microcephaly and Steroid‐Resistant Nephrotic Syndrome . Our previous study has indicated that Nup107 complex is significantly increased in infarcted myocardial tissues in rat …”

The roles of the nuclear pore complex in cellular dysfunction, aging and disease

“…The scaffold nucleoporin Nup35 has been shown to regulate intracellular cardiomyocyte pH by controlling the mRNA export of the Na + –H + exchanger- 1 (NHE1) transcript [163]. NHE1 protein is responsible for maintaining intracellular pH [164].…”

“…In response to an acid challenge cardiomyocytes deficient in Nup35 failed to maintain intracellular pH homeostasis and overexpression of Nup35 blocked hypoxia-induced intracellular acidification. Both Nup35 and NHE1 are downregulated in ischemic cardiomyocytes [163]. …”

Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis

“…Activation of NHE1 could induce cardiac hypertrophy and unbalanced cardiomyocyte pH, which may lead to myocardial remodeling and ischemic cardiac diseases [145,146,147]. SGK1 presumably phosphorylates NHE1 at Ser-703, promoting 14-3-3 binding and stimulating NHE1 activity by decreasing dephosphorylation and by stabilizing an active conformation of the exchanger [50,143].…”