A sodium zinc exchange mechanism is mediating extrusion of zinc in mammalian cells.
Zinc influx, driven by a steep inward electrochemical gradient, plays a fundamental role in zinc signaling and in pathophysiologies linked to intracellular accumulation of toxic zinc. Yet, the cellular transport mechanisms that actively generate or maintain the transmembrane gradients are not well understood. We monitored Na+-dependent Zn2+ transport in HEK293 cells and cortical neurons, using fluorescent imaging. Treatment of the HEK293 cells with CaPO4 precipitates induced Na+-dependent Zn2+ extrusion, against a 500-fold transmembrane zinc gradient, or zinc influx upon reversal of Na+ gradient, thus indicating that Na+/Zn2+ exchange is catalyzing active Zn2+ transport. Depletion of intracellular ATP did not inhibit the Na+-dependent Zn2+ extrusion, consistent with a mechanism involving a secondary active transporter. Inhibitors of the Na+/Ca2+ exchanger failed to inhibit Na+-dependent Zn2+ efflux. In addition, zinc transport was unchanged in HEK293 cells heterologously expressing functional cardiac or neuronal Na+/Ca2+ exchangers, thus indicating that the Na+/Zn2+ exchange activity is not mediated by the Na+/Ca2+ exchanger. Sodium-dependent zinc exchange, facilitating the removal of intracellular zinc, was also monitored in neurons. To our knowledge, the Na+/Zn2+ exchanger described here is the first example of a mammalian transport mechanism capable of Na+-dependent active extrusion of zinc. Such mechanism is likely to play an important role, not only in generating the transmembrane zinc gradients, but also in protecting cells from the potentially toxic effects of permeation of this ion.
Department of Physiology, Faculty of Health Science, Ben Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel.
Ehud
E
Ohana
Dror
D
Segal
Raz
R
Palty
Dien
D
Ton-That
Arie
A
Moran
Stefano L
SL
Sensi
John H
JH
Weiss
Michal
M
Hershfinkel
Israel
I
Sekler
D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D005456:Fluorescent Dyes; D016257:Fura-2; D006801:Humans; D017136:Ion Transport; D007700:Kinetics; D009474:Neurons / Q000378:metabolism; D010940:Plant Proteins; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D027682:Cation Transport Proteins; D018076:DNA, Complementary; D005456:Fluorescent Dyes; D010940:Plant Proteins; D011994:Recombinant Proteins; C485803:Slc30a1 protein, mouse; D019831:Sodium-Calcium Exchanger; C408070:ZNT1 zinc transporter, Thlaspi caerulescens; D012964:Sodium; D015032:Zinc; D016257:Fura-2