title: Unconventional chemiosmotic coupling of NHA2, a mammalian Na+/H+ antiporter, to a plasma membrane H+ gradient.
abstract: Human NHA2, a newly discovered cation proton antiporter, is implicated in essential hypertension by gene linkage analysis. We show that NHA2 mediates phloretin-sensitive Na(+)-Li(+) counter-transport (SLC) activity, an established marker for hypertension. In contrast to bacteria and fungi where H(+) gradients drive uptake of metabolites, secondary transport at the plasma membrane of mammalian cells is coupled to the Na(+) electrochemical gradient. Our findings challenge this paradigm by showing coupling of NHA2 and V-type H(+)-ATPase at the plasma membrane of kidney-derived MDCK cells, resulting in a virtual Na(+) efflux pump. Thus, NHA2 functionally recapitulates an ancient shared evolutionary origin with bacterial NhaA. Although plasma membrane H(+) gradients have been observed in some specialized mammalian cells, the ubiquitous tissue distribution of NHA2 suggests that H(+)-coupled transport is more widespread. The coexistence of Na(+) and H(+)-driven chemiosmotic circuits has implications for salt and pH regulation in the kidney.
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Kondapalli
authors.forename: Laura M
authors.initials: LM
authors.lastname: Kallay
authors.forename: Melanie
authors.initials: M
authors.lastname: Muszelik
authors.forename: Rajini
authors.initials: R
authors.lastname: Rao
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D018892:Proton-Motive Force / Q000502:physiology*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017920:Antiporters; C527589:SLC9B2 protein, human; D025262:Vacuolar Proton-Translocating ATPases