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Biological studies of organellar (Na⁺,K⁺)/H⁺ exchanger NHE7 Lin, Paulo J. C.


Cellular pH homeostasis plays crucial roles in cellular functions, and it is now widely recognized that Na⁺/H⁺ exchangers are among the most prominent players in this process. Although recently described mammalian Na⁺/H⁺ exchanger NHE7 has attracted much attention, its biological functions remain largely unknown. Most proteins exist as protein complexes in the cell and elicit their unique functions in collaboration with their binding partners. Therefore, identification and characterization of binding proteins will often unveil unexpected functions of the protein of interest. To begin to elucidate biological roles of the novel class of Na⁺/H⁺ exchanger NHE7, yeast two-hybrid screening was conducted and several binding candidates were identified. Among these candidates, I show that Secretory Carrier Membrane Proteins (SCAMPs) are novel NHE7 binding proteins and that SCAMPs regulate endocytic trafficking of NHE7 from the recycling endosomes to the trans-Golgi network (TGN). In agreement with this finding, I found that NHE7 can also be targeted to the plasma membrane and then internalized. Caveolins, structural proteins for caveolae, were identified as NHE7-binding proteins and it was initially hypothesized that caveolins might regulate NHE7-internalization. Interestingly, caveolins bound to NHE7 through a novel binding domain and facilitated its association to caveolae/lipid rafts, but did not affect NHE7-internalization. I also show that SCAMP2 associates with the heterotrimeric G protein β subunit (Gβ) and regulates the ERK1/2 signaling. Moreover, NHE7 was found to associate with both SCAMP2 and Gβ in the cell, suggesting that ERK1/2 signaling mediated by the SCAMP2-Gβ complex might regulate NHE7.

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