Na+/H+ exchanger isoform 5 (NHE5) is a brain-enriched NHE that may play important roles in ion homeostasis and cell-volume regulation. However, the regulation mechanism of NHE5 has not been fully elucidated. Here, we show that Receptor for Activated C-kinase 1 (RACK1) directly binds to NHE5 and positively regulates the transporter function. NHE5 co-localized with RACK1 as well as beta1 integrin, paxillin and vinculin, suggesting that NHE5 associates with focal adhesions. By using RACK1 dominant-negative mutants and siRNA, we further show that RACK1 regulates NHE5 both directly and through an integrin-dependent pathway. The NHE5-RACK1 interaction, but not the RACK1-beta1 integrin interaction, was reinforced when cells were spread on an integrin-substrate fibronectin. We propose that RACK1 activates NHE5 both by integrin-dependent and independent pathways, which may coordinate cellular ion homeostasis during cell-matrix adhesion.
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