# Structural determinants and pharmacological modulation of synaptic GEFs and GAPs

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2024 · $650,307

## Abstract

SUMMARY - PROJECT 1
The goal of this Center is to understand how gene expression and associated gene function within key neuronal
subtypes regulates the neurobiological substrates required to form cortical circuits that enable decision-making
and behavioral adaptations (i.e., behavioral circuits). Fitting with this theme, Project 1 will investigate the biology
of synaptic GEFs and GAPs at the molecular/biochemical and cellular levels. GEFs and GAPs are complex
multidomain proteins with multiple splice variants. Their protein domains perform enzymatic catalysis, subcellular
targeting, and autoregulation. Such domain combinatorial complexity can further specialize function to various
subcellular compartments, neuronal subtypes, and developmental time-points. Project 1 will test the hypothesis
that a structure-function analyses of isoforms, domains, and clinical variants will reveal mechanisms of
protein regulation that underlie neuronal morphogenesis, synapse formation, and synapse plasticity. We
recently developed novel high- and medium-throughput assays to characterize the modulation of GEF/GAP
catalytic activity and neuronal function by single nucleotide variants and chemical probes. Using these, we
will delineate GEF and GAP spatiotemporal complexity by dissecting the roles of splice variants, enzymatic
domains, and non-catalytic domains at the molecular and cellular levels. Additionally, Project 1 will develop
chemical probes which will be utilized to further define their biological function in Projects 2-4. Spatiotemporal
and GTPase activity analyses will identify critical periods and cell/tissue specificity for biological activity and
genetic and pharmacological manipulation to inform Projects 2–4. Mutation-driven structure-function analysis
will reveal mechanistic insight to guide iPSC and mouse studies in Projects 2–4. Chemical probes will be
highly valuable in Projects 2–4 and for the field. Data generated will reveal novel mechanism of function and
regulation to provide a conceptual framework for the large family of > 180 Ras/Rho GEF/GAPs, with broad
implications.

## Key facts

- **NIH application ID:** 10862385
- **Project number:** 1P50MH132775-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peter Penzes
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,307
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862385

## Citation

> US National Institutes of Health, RePORTER application 10862385, Structural determinants and pharmacological modulation of synaptic GEFs and GAPs (1P50MH132775-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862385. Licensed CC0.

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