Open AccessAberrant dynamin 2‐dependent Na + /H + exchanger‐1 trafficking contributes to cardiomyocyte apoptosis
Author(s) -
Li Jun,
Xu Liang,
Ye Jiangchuan,
Li Xiang,
Zhang Dasheng,
Liang Dandan,
Xu Xinran,
Qi Man,
Li Changming,
Zhang Hong,
Wang Jing,
Liu Yi,
Zhang Yuzhen,
Zhou Zhaonian,
Liang Xingqun,
Li Jue,
Peng Luying,
Zhu Weidong,
Chen YiHan
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12086
Subject(s) - apoptosis , microbiology and biotechnology , dynamin , chemistry , physics , biology , cell , biochemistry , endocytosis
Sarcolemmal Na + / H + exchanger 1 ( NHE 1) activity is essential for the intracellular pH (pH i ) homeostasis in cardiac myocytes. Emerging evidence indicates that sarcolemmal NHE 1 dysfunction was closely related to cardiomyocyte death, but it remains unclear whether defective trafficking of NHE 1 plays a role in the vital cellular signalling processes. Dynamin ( DNM ), a large guanosine triphosphatase ( GTP ase), is best known for its roles in membrane trafficking events. Herein, using co‐immunoprecipitation, cell surface biotinylation and confocal microscopy techniques, we investigated the potential regulation on cardiac NHE 1 activity by DNM . We identified that DNM 2, a cardiac isoform of DNM , directly binds to NHE 1. Overexpression of a wild‐type DNM 2 or a dominant‐negative DNM 2 mutant with defective GTP ase activity in adult rat ventricular myocytes ( ARVM s) facilitated or retarded the internalization of sarcolemmal NHE 1, whereby reducing or increasing its activity respectively. Importantly, the increased NHE 1 activity associated with DNM 2 deficiency led to ARVM s apoptosis, as demonstrated by cell viability, terminal deoxynucleotidyl transferase–mediated dUTP nick‐end labelling assay, Bcl‐1/Bax expression and caspase‐3 activity, which were effectively rescued by pharmacological inhibition of NHE 1 with zoniporide. Thus, our results demonstrate that disruption of the DNM 2‐dependent retrograde trafficking of NHE 1 contributes to cardiomyocyte apoptosis.