A mechanism for the activation of the Na/H exchanger NHE-1 by cytoplasmic acidification and mitogens.
Eukaryotic cells constantly have to fight against internal acidification. In mammals, this task is mainly performed by the ubiquitously expressed electroneutral Na(+)/H(+) exchanger NHE-1, which activates in a cooperative manner when cells become acidic. Despite its biological importance, the mechanism of this activation is still poorly understood, the most commonly accepted hypothesis being the existence of a proton-sensor site on the internal face of the transporter. This work uncovers mutations that lead to a nonallosteric form of the exchanger and demonstrates that NHE-1 activation is best described by a Monod-Wyman-Changeux concerted mechanism for a dimeric transporter. During intracellular acidification, a low-affinity form of NHE-1 is converted into a form possessing a higher affinity for intracellular protons, with no requirement for an additional proton-sensor site on the protein. This new mechanism also explains the activation of the exchanger by growth signals, which shift the equilibrium towards the high-affinity form.
Lacroix
Jérôme
J
Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Nice-Sophia Antipolis, CNRS UMR 6548, Parc Valrose, 06108 Nice cedex 2, France.
Poët
Mallorie
M
Maehrel
Céline
C
Counillon
Laurent
L
D001483:Base Sequence; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003600:Cytosol / Q000378:metabolism*; D006133:Growth Substances / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D016895:Culture Media, Serum-Free; D006133:Growth Substances; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1