ZIP-ZnT1 complexes mediate a local Zn2+-cycle regulating neuronal Zn²⁺ transport

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Abstract
ZnT1 is the main transporter mediating Zn²⁺ efflux from the cytoplasm to the extracellular space. Paradoxically, due to relatively low Zn2+ affinity of ZnT1, physiological levels of cytoplasmic free Zn2+ are seemingly insufficient to support ZnT1 function. However, physiological modulation of NMDA receptor responses by synaptically released Zn2+ requires a Zn2+ rise in the postsynaptic neurons, accompanied by ZnT1 activity. We hypothesized that Zn2+ import from the extracellular space could generate intracellular Zn2+ microdomains in the vicinity of ZnT1 to enable its activity, thus forming a localized "Zn2+-cycle." To identify the functional machinery that may drive this process, we investigated the expression and function of ZIP proteins that import Zn2+ into the neuronal cytoplasm. We focused on the dorsal cochlear nucleus (DCN) and hippocampus, regions where synaptic Zn2+ modulates postsynaptic NMDA responses and synaptic plasticity. We demonstrate that ZIP3 is expressed on DCN cartwheel cells and required for postsynaptic Zn2+ influx. Importantly, ZIP3 physically interacts with ZnT1, suggesting that it is an integral component of the synaptic Zn2+-cycle machinery. In the hippocampus, ZIP1, but not ZIP3, mediates Zn2+ import into postsynaptic CA3 cells and we find that ZIP1 interacts with ZnT1 in this brain region. Importantly, Zn2+ efflux rates are enhanced in SH-SY5Y cells co-expressing ZnT1 and either ZIP3 or ZIP1, compared to rates in cells expressing ZnT1 alone. Our findings indicate that ZnT1-dependent Zn2+ efflux is facilitated by ZIP-ZnT1 complexes, which potentially induce local intracellular Zn2+ microdomains supporting a Zn2+-cycle capable of modulating synaptic signaling.
Funding Information
  • United States - Israel Binational Science Foundation (2023045)
  • United States - Israel Binational Science Foundation (2023045)
  • United States - Israel Binational Science Foundation (2023045)
  • National Institute of Health (DC020923)
  • Israel Science Foundation (812/20)

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