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Molecular mechanisms of non‐transferrin‐bound and transferring‐bound iron uptake in primary hippocampal neurons
Author(s) -
Ji Changyi,
Kosman Daniel J.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13040
Subject(s) - dmt1 , transferrin , transferrin receptor , hippocampal formation , chemistry , ferrous , transporter , endocytosis , receptor , biochemistry , ferroportin , biophysics , microbiology and biotechnology , metabolism , biology , endocrinology , gene , organic chemistry , iron homeostasis
Abstract The molecular mechanisms of iron trafficking in neurons have not been elucidated. In this study, we characterized the expression and localization of ferrous iron transporters Zip8, Zip14 and divalent metal transporter 1 ( DMT 1), and ferrireductases Steap2 and stromal cell‐derived receptor 2 in primary rat hippocampal neurons. Steap2 and Zip8 partially co‐localize, indicating these two proteins may function in Fe 3+ reduction prior to Fe 2+ permeation. Zip8, DMT 1, and Steap2 co‐localize with the transferrin receptor/transferrin complex, suggesting they may be involved in transferrin receptor/transferrin‐mediated iron assimilation. In brain interstitial fluid, transferring‐bound iron ( TBI ) and non‐transferrin‐bound iron ( NTBI ) exist as potential iron sources. Primary hippocampal neurons exhibit significant iron uptake from TBI (Transferrin‐ 59 Fe 3+ ) and NTBI , whether presented as 59 Fe 2+ ‐citrate or 59 Fe 3+ ‐citrate; reductase‐independent 59 Fe 2+ uptake was the most efficient uptake pathway of the three. Kinetic analysis of Zn 2+ inhibition of Fe 2+ uptake indicated that DMT 1 plays only a minor role in the uptake of NTBI . In contrast, localization and knockdown data indicate that Zip8 makes a major contribution. Data suggest also that cell accumulation of 59 Fe from TBI relies at least in part on an endocytosis‐independent pathway. These data suggest that Zip8 and Steap2 play a major role in iron accumulation from NTBI and TBI by hippocampal neurons.Analysis of the expression and localization of known iron uptake transporters demonstrated that Zip8 makes a major contribution to iron accumulation in primary cultures of rat embryonic hippocampal neurons. These cells exhibit uptake pathways for ferrous and ferric iron (non‐transferrin‐bound iron, NTBI in figure) and for transferrin‐bound iron; the ferrireductases Steap2 and SDR2 support the uptake of ferric iron substrates. Zip8 and Steap2 are strongly expressed in the plasma membrane of both soma and processes, implying a crucial role in iron accumulation from NTBI and transferrin‐bound iron (TBI) by hippocampal neurons.