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The Na+/H+ exchanger, NHE1, differentially regulates mitogen‐activated protein kinase subfamilies after osmotic shrinkage in Ehrlich Lettre Ascites cells
Author(s) -
Pedersen Stine Falsig,
Darborg Barbara,
Rasmussen Maria,
Hoffmann Else
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a963-d
Subject(s) - mapk/erk pathway , kinase , intracellular ph , chemistry , protein kinase a , p38 mitogen activated protein kinases , extracellular , intracellular , sodium–hydrogen antiporter , microbiology and biotechnology , biochemistry , biology , sodium , organic chemistry
Osmotic shrinkage modulates the activity of mitogen activated protein kinases (MAPKs) by incompletely elucidated mechanisms. Here, we address the possible roles of the Na + /H + exchanger, NHE1, in shrinkage‐induced MAPK regulation. Osmotic shrinkage of Ehrlich Lettre Ascites (ELA) cells in HCO 3 − ‐free medium elicited regulatory volume increase and intracellular alkalinization, both blocked by the NHE1 inhibitor EIPA. Osmotic shrinkage rapidly and transiently inhibited Extracellular signal Regulated Kinase (ERK1/2), and activated p38 MAPK and c‐Jun N‐terminal kinase (JNK1/2). ERK inhibition by shrinkage was reversed by NHE1 inhibitors (EIPA, HOE642), and by Na + o removal, and ERK activity in NHE1 deficient AP1 cells was strongly attenuated by human (h)NHE1 expression. The effect of NHE1 on ERK was at least in part upstream of MEK1/2, which was also shrinkage‐inhibited in an EIPA sensitive manner. Shrinkage‐induced p38 MAPK activation was EIPA insensitive. Shrinkage‐induced JNK activation was attenuated by EIPA, was augmented in AP1 cells by hNHE1 expression, and was, in contrast to the changes in p38 MAPK or ERK activity, dependent on NHE1‐mediated intracellular alkalinization. Shrinkage‐induced cell death was augmented by inhibition of NHE1, ERK, or JNK, and attenuated by inhibition of p38 MAPK. It is suggested that isoform‐specific modulation of MAPK activity is an important physiological role of NHE1.