# Liberation of Intracellular Zinc and Neuronal Cell Death

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $569,656

## Abstract

This grant proposal represents the third competitive renewal (Years 16-20) of a highly productive research
program investigating fundamental cellular and molecular signaling pathways relevant to human
neurodegenerative disorders. Over the last 15 years of funding from this grant, our studies have characterized
in detail a signaling cascade connecting the oxidative liberation of intracellular zinc to a neuronal cell death-enabling increase in the plasma membrane insertion of Kv2.1 channels. This process mediates a loss of
cytoplasmic potassium, a requisite step for optimal protease and nuclease catalytic activity during programmed
and other forms of cell death. In the current funding period (Years 11-15), we have studied the
phosphorylation events leading to the syntaxin-dependent exocytotic insertion of Kv2.1 into the neuronal
plasma membrane following injury. We also investigated the role of Kv2.1 somatodendritic clusters as
dominant membrane channel insertion hubs during apoptosis. Most importantly, we established a novel in vivo
neuroprotective approach to stroke injury by developing a cell-permeant peptide that interferes with a critical
Kv2.1 interaction with syntaxin. Our work strongly indicates that specifically targeting Kv2.1-facilitated cell
death processes can provide mechanistically driven, novel therapeutic strategies for neuroprotection. In this
application we propose to decisively move forward with this strategic objective by: (i) characterizing the
properties of novel neuroprotective peptides and derived small molecule analogs targeting the
syntaxin/Kv2.1 interaction; (ii) establishing prototypical neuroprotective tools aimed at dispersing Kv2.1
somatodendritic clusters, and (iii) devising an innovative neuroprotective strategy that transfers a normally
silent gene to neurons, designed to express a Kv2.1-targeted modulatory protein when cells are lethally
injured. We thus have adopted three unique and potentially transformative strategies, all based on the
premise that cell death-inducing pathways require a set of common conditions to operate optimally. The loss
of intracellular potassium via a surge of Kv2.1-mediated ionic currents may constitute a widespread, if not
ubiquitous, requirement for programmed cell death in many types of neurons. As such, the experiments
described here are aimed at translating the cellular and molecular pathways we have characterized with
long-term funding from this grant, into rational therapeutic approaches to neurodegeneration.

## Key facts

- **NIH application ID:** 10200152
- **Project number:** 5R01NS043277-19
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Elias Aizenman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,656
- **Award type:** 5
- **Project period:** 2002-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200152

## Citation

> US National Institutes of Health, RePORTER application 10200152, Liberation of Intracellular Zinc and Neuronal Cell Death (5R01NS043277-19). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10200152. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*