Upregulation of NMDA Receptor Function by a GluN2A/ZnT1-directed Peptide

Zinc is a dynamic signaling element in the brain, critically contributing to sensory processing and synaptic plasticity. The zinc transporter ZnT3 packages it into synaptic vesicles of large populations of excitatory neurons throughout the brain. Zinc is thus co-released with glutamate during synaptic transmission, influencing the activity of the NMDA receptor. The Aizenman and Tzounopoulos laboratories described that another zinc transporter, namely ZnT1, by interacting with the NMDA receptor subunit GluN2A, strongly influence the actions of synaptically released zinc on the receptor.

Description

Researchers designed a cell and blood-brain-barrier permeable peptide termed TAT-N2AZ aimed at disrupting the ZnT1-GluN2A interaction. They observed that in the presence of the peptide, but not a control scramble, NMDA receptor activation was enhanced by decreasing the inhibitory actions of synaptically-released zinc. This is the first tool developed to enhance NMDA receptor function via a previous undescribed mechanism and may be useful in the treatment of disorders associated with NMDA receptor hypofunction, such as schizophrenia.

Applications

· Treating schizophrenia and other disorders associated with NMDA receptor hypofunction

Advantages

· Works via a previously unknown mechanism

Invention Readiness

In vitro data

IP Status

https://patents.google.com/patent/US20230034660A1

Related Publication(s)

Krall, R., Gale, J. R., Ross, M. M., Tzounopoulos, T., & Aizenman, E. (2022). Intracellular zinc signaling influences NMDA receptor function by enhancing the interaction of ZnT1 with GluN2A. Neuroscience Letters, 790, 136896. https://doi.org/10.1016/j.neulet.2022.136896

Krall, R. F., Moutal, A., Phillips, M. B., Asraf, H., Johnson, J. W., Khanna, R., Hershfinkel, M., Aizenman, E., & Tzounopoulos, T. (2020). Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1. Science Advances, 6(27). https://doi.org/10.1126/sciadv.abb1515