ZnT3

ZnT3, short for zinc transporter 3, is a member of the ZnT (SLC30) family of metal ion transporters and is encoded by the SLC30A3 gene. It functions to move zinc ions from the cytosol into synaptic vesicles in neurons, contributing to the brain’s vesicular zinc pool that is released during neurotransmission.

ZnT3 is predominantly expressed in the forebrain, with high levels in regions such as the hippocampus and cortex. Its protein product localizes to synaptic vesicle membranes, where zinc is packaged for activity-dependent release alongside neurotransmitters.

Mechanistically, ZnT3 uses the proton motive force to transport Zn2+ into vesicles, effectively reducing cytosolic zinc and loading zinc into vesicles for rapid release during synaptic activity. The released zinc can modulate postsynaptic receptors and ion channels, influencing neuronal excitability and synaptic signaling.

Physiologically, vesicular zinc acts as a neuromodulator. ZnT3-mediated zinc release participates in regulating synaptic plasticity, learning, and memory, and may shape the balance of excitatory and inhibitory signaling in neural networks.

Genetic and clinical relevance is highlighted by ZnT3 knockout models, which lack vesicular zinc in forebrain neurons and show alterations in synaptic plasticity and certain learning tasks. Altered zinc homeostasis in the brain has been explored in relation to neurodegenerative diseases, including potential effects on amyloid precursor protein processing and amyloid pathology in relevant animal models. Overall, ZnT3 is an essential component of brain zinc homeostasis with implications for neural signaling and cognitive function, and its study continues to inform understanding of metal ion regulation in health and disease.