Open AccessNa/H exchanger NHE1 acts upstream of rho GTPases to promote neurite outgrowth
Author(s) -
Sin Wun Chey,
Tam Nicola,
Moniz David,
Lee Connie,
Church John
Publication year - 2020
Publication title -
journal of cell communication and signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 44
eISSN - 1873-961X
pISSN - 1873-9601
DOI - 10.1007/s12079-020-00556-5
Subject(s) - rhoa , neurite , gtpase , microbiology and biotechnology , rac1 , cdc42 , lysophosphatidic acid , small gtpase , guanine nucleotide exchange factor , morphogenesis , chemistry , activator (genetics) , biology , signal transduction , biochemistry , receptor , gene , in vitro
Na + /H + exchanger NHE1, a major determinant of intracellular pH (pH i ) in mammalian central neurons, promotes neurite outgrowth under both basal and netrin‐1‐stimulated conditions. The small GTP binding proteins and their effectors have a dominant role in netrin‐1‐stimulated neurite outgrowth. Since NHE1 has been shown previously to work downstream of the Rho GTPases‐mediated polarized membrane protrusion in non‐neuronal cells, we examined whether NHE1 has a similar relationship with Cdc42, Rac1 and RhoA in neuronal morphogenesis. Interestingly, our results suggest the possibility that NHE1 acting upstream of Rho GTPases to promote neurite outgrowth induced by netrin‐1. First, we found that netrin‐1‐induced increases in the activities of Rho GTPases using FRET (Forster Resonance Energy Transfer) analyses in individual growth cones; furthermore, their increased activities were abolished by cariporide, a specific NHE1 inhibitor. Second, NHE1 inhibition had no effect on neurite retraction induced by L‐α‐Lysophosphatidic acid (LPA), a potent RhoA activator. The regulation of Rho GTPases by NHE1 was further evidenced by reduced Rac1, Cdc42 and RhoA activities in NHE1‐null neurons. Taken together, our findings suggest that NHE1‐dependent neuronal morphogenesis involves the activation of Rho‐family of small GTPases.