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Lithium interactions with Na+-coupled inorganic phosphate cotransporters: insights into the mechanism of sequential cation binding


Andrini, Olga; Meinild, Anne-Kristine; Ghezzi, Chiara; Murer, Heini; Forster, Ian C (2012). Lithium interactions with Na+-coupled inorganic phosphate cotransporters: insights into the mechanism of sequential cation binding. American Journal of Physiology. Cell Physiology, 302(3):C539-C554.

Abstract

Type IIa/b Na(+)-coupled inorganic phosphate cotransporters (NaPi-IIa/b) are considered to be exclusively Na(+) dependent. Here we show that Li(+) can substitute for Na(+) as a driving cation. We expressed NaPi-IIa/b in X. laevis oocytes and performed two-electrode voltage-clamp electrophysiology and uptake assays to investigate the effect of external Li(+) on their kinetics. Replacement of 50% external Na(+) with Li(+) reduced the maximum transport rate and the rate-limiting plateau of the Pi-induced current began at less hyperpolarizing potentials. Simultaneous electrophysiology and 22Na uptake on single oocytes revealed that Li(+) ions can substitute for at least one of the 3 Na(+) ions necessary for cotransport. Presteady-state assays indicated that Li(+) ions alone interact with the empty carrier, however the total charge displaced was 70% of that with Na(+) alone, or when 50% of the Na(+) was replaced by Li(+). If Na(+) and Li(+) were both present, the midpoint potential of the steady-state charge distribution was shifted towards depolarizing potentials. The charge movement in the presence of Li(+) alone reflected the interaction of one Li(+) ion, in contrast to 2 Na(+) ions when only Na was present. We propose an ordered binding scheme for cotransport in which Li(+) competes with Na+ to occupy the putative 1st cation interaction site, followed by the cooperative binding of one Na(+) ion, one divalent Pi anion and a 3rd Na(+) ion to complete the carrier loading. With Li(+) bound, the kinetics of subsequent partial reactions were significantly altered. Kinetic simulations of this scheme support our experimental data.

Type IIa/b Na(+)-coupled inorganic phosphate cotransporters (NaPi-IIa/b) are considered to be exclusively Na(+) dependent. Here we show that Li(+) can substitute for Na(+) as a driving cation. We expressed NaPi-IIa/b in X. laevis oocytes and performed two-electrode voltage-clamp electrophysiology and uptake assays to investigate the effect of external Li(+) on their kinetics. Replacement of 50% external Na(+) with Li(+) reduced the maximum transport rate and the rate-limiting plateau of the Pi-induced current began at less hyperpolarizing potentials. Simultaneous electrophysiology and 22Na uptake on single oocytes revealed that Li(+) ions can substitute for at least one of the 3 Na(+) ions necessary for cotransport. Presteady-state assays indicated that Li(+) ions alone interact with the empty carrier, however the total charge displaced was 70% of that with Na(+) alone, or when 50% of the Na(+) was replaced by Li(+). If Na(+) and Li(+) were both present, the midpoint potential of the steady-state charge distribution was shifted towards depolarizing potentials. The charge movement in the presence of Li(+) alone reflected the interaction of one Li(+) ion, in contrast to 2 Na(+) ions when only Na was present. We propose an ordered binding scheme for cotransport in which Li(+) competes with Na+ to occupy the putative 1st cation interaction site, followed by the cooperative binding of one Na(+) ion, one divalent Pi anion and a 3rd Na(+) ion to complete the carrier loading. With Li(+) bound, the kinetics of subsequent partial reactions were significantly altered. Kinetic simulations of this scheme support our experimental data.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:04 Apr 2012 06:47
Last Modified:05 Apr 2016 15:27
Publisher:American Physiological Society
ISSN:0363-6143
Publisher DOI:https://doi.org/10.1152/ajpcell.00364.2011
PubMed ID:22075694
Permanent URL: https://doi.org/10.5167/uzh-56347

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