A cell and blood-brain barrier permerable peptide aimed at disrupting the ZnT1-GluN2A interaction.
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.
Technology 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.Advantages
Works via a previously unknown mechanismApplications
Treating schizophrenia and other disorders associated with NMDA receptor hypofunctionStage of Development
In vitro dataIP Status
Provisional patent application number 62/942,979 filed.Relevant Publications
Krall RF, Moutal A, Phillips MB, Asraf H, Johnson JW, Khanna R, Hershfinkel M, Aizenman E, Tzounopoulos T. Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1. Sci Adv. 2020 Jul 3;6(27):eabb1515. doi: 10.1126/sciadv.abb1515. PMID: 32937457; PMCID: PMC7458442.
InnovatorsElias Aizenman, PhD
Professor of Neurobiology
Dr. Aizenman’s research focuses on investigating cellular signaling processes leading to NMDA receptor regulation, neuronal cell death, and devising novel approaches to neuroprotection. He has been funded continuously by NIH R01 mechanisms for over 30 years and has been awarded several patents. He has recently partnered with a small biopharmaceutical firm to advance a novel neuroprotective peptide to the clinic. He was awarded the Charles E. Kaufman New Initiative Award in 2016 and was chair of the NOMD NIH study section in 2018.Education
Postdoctoral, Neuroscience, Harvard Medical School
PhD, Toxicology, Johns Hopkins University
BS, Biology, Boston UniversityRecent Publications
Krall, R.F., T. Tzounopoulos and E. Aizenman. The function and regulation of zinc in the brain. Neuroscience. 2021 (in press).
Yeh, C., Schulien, A., Molyneaux, B., Aizenman, E. Lessons from Recent Advances in Ischemic Stroke Management and Targeting Kv2.1 for Neuroprotection. International Journal of Molecular Sciences. 2020 Aug 25;21(17):E6107. DOI: 10.3390/ijms21176107.
Aizenman, E., R.H. Loring, I.J. Reynolds and P.A. Rosenberg. The redox biology of excitotoxic processes: the NMDA receptor, TOPA quinone, and the oxidative liberation of intracellular zinc. Frontiers in Neuroscience - Special Issue: Excitotoxicity Turns 50. 2020, 14:778, DOI: 10.3389/fnins.2020.00778.
Schulien, A.J., C.-Y Yeh, B.N. Orange, O.J. Pav, M.P. Hopkins, A. Moutal, R. Khanna, D. Sun, J.A. Justice* and E. Aizenman.* Targeted-disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels. Science Advances 01 Jul 2020: Vol. 6, no. 27, eaaz8110; DOI: 10.1126/sciadv.aaz8110 .
Krall, R.F., A. Moutal, M.B. Phillips, H. Asraf, J.W. Johnson, R. Khanna, M. Hershfinkel, E. Aizenman* and T. Tzounopoulos.* Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1. Science Advances 03 Jul 2020: Vol. 6, no. 27, eabb1515; DOI: 10.1126/sciadv.abb1515Thanos Tzounopolous, PhD
Professor and Vice Chair of Research, Department of Otolaryngology
UPMC Endowed Professor of Auditory Physiology
Directory, Pittsburgh Hearing Research Center
Dr. Tzounopoulos’s research focuses on the synaptic and intrinsic properties and plasticity of brain circuits and neurons as well as the pursuit of drug discovery and development for tinnitus and hearing loss.Education
PhD, Vollum Institute, Oregon Health and Science UniversityRecent Publications
Laura Marinos, Stylianos Kouvaros, Brandon Bizup, Bryce Hambach, Peter Wipf, Thanos Tzounopoulos (2021).Transient Delivery of KCNQ2/3-Specific Channel Activator One Week after Noise Trauma Mitigates Noise-Induced Tinnitus. JARO 2021 (In Press)
Rebecca F. Krall, Aubin Moutal, Matthew B. Phillips, Hila Asraf, Jon W. Johnson, Rajesh Khanna, Michal Hershfinkel, Elias Aizenman, and Thanos Tzounopoulos (2020). Synaptic Zinc Inhibition of NMDA Receptors Depends on the Association of GluN2A with the Zinc Transporter ZnT1. Science Advances. 03 Jul 2020: EABB1515. DOI: 10.1126/SCIADV.ABB1515
Vogler NW, Betti VM, Goldberg JM, Tzounopoulos T (2020). Mechanisms Underlying Long-Term Synaptic Zinc Plasticity at Mouse Dorsal Cochlear Nucleus Glutamatergic Synapses. J Neurosci. 2020;JN-RM-0175-20. doi:10.1523/JNEUROSCI.0175-20.2020. J Neurosci. 2020;JN-RM-0175-20. doi:10.1523/JNEUROSCI.0175-20.2020
Stylianos Kouvaros, Manoj Kumar, and Thanos Tzounopoulos (2020). Synaptic Zinc Enhances Inhibition Mediated by Somatostatin, but not Parvalbumin, Cells in Mouse Auditory Cortex. Cereb Cortex. 2020;30(7):3895-3909.
Thanos Tzounopoulos, Carey Balaban, Lori Zitelli, and Catherine Palmer (2019). Towards a Mechanistic-Driven Precision Medicine Approach for Tinnitus. J Assoc Res Otolaryngol. 2019 Apr;20(2):115-131. doi: 10.1007/s10162-018-00709-9. Epub 2019 Mar 1.