Reassessment of the transport mechanism of the human zinc transporter SLC39A2

Franz, Marie-Christine; Pujol Gimenez, Jonai; Montalbetti, Nicolas; Fernandez Tenorio, Miguel; DeGrado, Timothy R.; Niggli, Ernst; Romero, Michael F.; Hediger, Matthias (2018). Reassessment of the transport mechanism of the human zinc transporter SLC39A2. Biochemistry, 57(26), pp. 3976-3986. American Chemical Society 10.1021/acs.biochem.8b00511

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The human zinc transporter SLC39A2, also known as ZIP2, was shown to mediate zinc transport that could be inhibited at pH values below 7.0 and stimulated by HCO3-, suggesting a Zn2+/HCO3- cotransport mechanism (1). In contrast, recent experiments in our laboratory indicated that the functional activity of ZIP2 increases at acidic pH (2). The present study was therefore designed to reexamine the findings on the pH-dependence and to extend the functional characterization of ZIP2. Our current results show that ZIP2-mediated transport is modulated by extracellular pH, but independent of the H+ driving force. Also, in our experiments, ZIP2-mediated transport is not modulated by extracellular HCO3-. Moreover, high extracellular [K+], which induces depolarization, inhibited ZIP2-mediated transport, indicating that the transport mechanism is voltage-dependent. We also show that ZIP2-mediates the uptake of Cd2+ (Km~ 1.57 µM) in a pH-dependent manner (KH+ of ~66 nM). Cd2+ transport is inhibited by extracellular [Zn2+] (IC50~ 0.32 µM), [Cu2+] (IC50~ 1.81 µM) and to a lower extend by [Co2+], but not by [Mn2+] or [Ba2+]. Fe2+ is not transported by ZIP2. Accordingly, the substrate selectivity of ZIP2 decreases in the order Zn2+ > Cd2+ ≥ Cu2+ > Co2+. Altogether, we propose that ZIP2 is a facilitated divalent metal ion transporter that can be modulated by extracellular pH and membrane potential. Given that ZIP2 expression has been reported in acidic environments (3-5), we suggest that the herein described H+-mediated regulatory mechanism might be important to determine the velocity and direction of the transport process.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology
04 Faculty of Medicine > Other Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Franz, Marie-Christine; Pujol Gimenez, Jonai; Montalbetti, Nicolas; Fernandez Tenorio, Miguel; Niggli, Ernst and Hediger, Matthias

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0006-2960

Publisher:

American Chemical Society

Language:

English

Submitter:

Kevin Marc Rupp

Date Deposited:

04 Jun 2018 09:19

Last Modified:

10 Dec 2018 15:02

Publisher DOI:

10.1021/acs.biochem.8b00511

PubMed ID:

29791142

BORIS DOI:

10.7892/boris.116853

URI:

https://boris.unibe.ch/id/eprint/116853

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