title: The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions.
abstract: 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.
authors.affiliation: Department of Stomatology, University of California, San Francisco, HSW 604, San Francisco, California 94143-0512, USA. lputney@itsa.ucsf.edu
authors.forename: L K
authors.initials: LK
authors.lastname: Putney
authors.forename: S P
authors.initials: SP
authors.lastname: Denker
authors.forename: D L
authors.initials: DL
authors.lastname: Barber
mesh_terms: 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*
chemical_list: D002147:Calmodulin; D017923:Sodium-Hydrogen Exchangers