Abstract
In the present work, the multiple-indicator dilution (MID) technique was used to investigate the kinetic mechanisms by which nickel (Ni2+) affects the calcium (Ca2+) transport in intact rat liver. 45Ca2+ and extra- and intracellular space indicators were injected in livers perfused with 1 mM Ni2+, and the outflow profiles were analyzed by a mathematical model. For comparative purposes, the effects of norepinephrine were measured. The influence of Ni2+ on the cytosolic Ca2+ concentration ([Ca2+]c) in human hepatoma Huh7 cells and on liver glycogen catabolism, a biological response sensitive to cellular Ca2+, was also evaluated. The estimated transfer coefficients of 45Ca2+ transport indicated two mechanisms by which Ni2+ increases the [Ca2+]c in liver under steady-state conditions: (1) an increase in the net efflux of Ca2+ from intracellular Ca2+ stores due to a stimulus of Ca2+ efflux to the cytosolic space along with a diminution of Ca2+ re-entry into the cellular Ca2+ stores; (2) a decrease in Ca2+ efflux from the cytosolic space to vascular space, minimizing Ca2+ loss. Glycogen catabolism activated by Ni2+ was transient contrasting with the sustained activation induced by norepinephrine. Ni2+ caused a partial reduction in the norepinephrine-induced stimulation in the [Ca2+]c in Huh7 cells. Our data revealed that the kinetic parameters of Ca2+ transport modified by Ni2+ in intact liver are similar to those modified by norepinephrine in its first minutes of action, but the membrane receptors or Ca2+ transporters affected by Ni2+ seem to be distinct from those known to be modulated by norepinephrine.
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This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—308980/2017–4) and Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES/NUFFIC n°14/10). Karina Sayuri Utsunomiya holds fellowship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico.
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KSU: Investigation, validation, formal analysis, writing—original draft. LJdS: Investigation, validation. JI: Investigation, validation. RPC: Visualization, writing—review and editing. EHG: Visualization. JC: Writing—review and editing. AB: Methodology, software. RPJOE: Supervision, writing—review and editing. ELI-I: Supervision, project administration, funding acquisition, writing—original draft, review and editing.
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Utsunomiya, K.S., da Silva, L.J., Iwamoto, J. et al. Kinetic mechanisms by which nickel alters the calcium (Ca2+) transport in intact rat liver. J Biol Inorg Chem 26, 641–658 (2021). https://doi.org/10.1007/s00775-021-01883-7
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DOI: https://doi.org/10.1007/s00775-021-01883-7