The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions.
The NHE family of ion exchangers includes six isoforms (NHE1-NHE6) that function in an electroneutral exchange of intracellular H(+) for extracellular Na(+). This review focuses on the only ubiquitously expressed isoform, NHE1, which is localized at the plasma membrane where it plays a critical role in intracellular pH (pHi) and cell volume homeostasis. All NHE isoforms share a similar topology: an N-terminus of 12 transmembrane (TM) alpha-helices that collectively function in ion exchange, and a C-terminal cytoplasmic regulatory domain that modulates transport activity by the TM domain. Extracellular signals, mediated by diverse classes of cell-surface receptors, regulate NHE1 activity through distinct signaling networks that converge to directly modify the C-terminal regulatory domain. Modifications in the C-terminus, including phosphorylation and the binding of regulatory proteins, control transport activity by altering the affinity of the TM domain for intracellular H(+). Recently, it was determined that NHE1 also functions as a membrane anchor for the actin-based cytoskeleton, independently of its role in ion translocation. Through its effects on pHi homeostasis, cell volume, and the actin cortical network, NHE1 regulates a number of cell behaviors, including adhesion, shape determination, migration, and proliferation.
Putney
L K
LK
Department of Stomatology, University of California, San Francisco, HSW 604, San Francisco, California 94143-0512, USA. lputney@itsa.ucsf.edu
Denker
S P
SP
Barber
D L
DL
D000818:Animals; D017209:Apoptosis; D002147:Calmodulin / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D003599:Cytoskeleton / Q000502:physiology; D006801:Humans; D010766:Phosphorylation; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*
D002147:Calmodulin; D017923:Sodium-Hydrogen Exchangers