# Small GTPase signaling in dendrites and spines

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2020 · $782,079

## Abstract

ABSTRACT
Dendritic and spine plasticity plays key roles in brain development, function, behavior, and disease. Indeed,
spine and dendrite pathology is a common feature of many neuropsychiatric disorders (NPDs), including
autism spectrum disorder (ASD), schizophrenia (SZ), and bipolar disorder (BPD). Rho-like small GTPases,
including Rac1, are a family of regulatory proteins with central roles in dendrite and spine plasticity. Their
extensive implication in NPDs suggests that these pathways can serve as therapeutic targets in NPDs. The
activity of small GTPases is enhanced by guanine-nucleotide-exchange factors (GEFs), among which the Rac1-
GEF kalirin is highly enriched in spines, and is perhaps the best-characterized GEF in the brain. Kalirin is a
central regulator of dendrite arborization, spine plasticity, glutamatergic transmission, neuronal connectivity,
and cognitive behavior. While small-molecule pharmacological modulators have been invaluable tools for
studying the biological functions of kinases, receptors, or ion channels, no such tools exist for Rho-GEFs,
including kalirin. Kalirin is an optimal drug target for several reasons: its expression is largely restricted to the
CNS, it is highly enriched in spines, it is a signaling hub in a synaptic network including many NPD risk factors,
its enzymatic activity can be modulated, and the 3D structure of its GEF domain has been determined. Here we
outline a novel and innovative hit validation cascade that will allow us to develop small-molecule tools to
investigate a previously unapproachable target relevant to NPDs. The brain-specific expression of kalirin and
its highly compartmentalized subcellular localization at synapses suggests that regulation of Rac1 signaling,
through pharmacological interventions targeting kalirin, may allow neuron- and synapse-specific effects. This
is key to developing tools that produce cell type-specific and context-dependent Rac1 modulation. Using a
combination of high-throughput screening (HTS) and in silico screening against the target proteins
kalirin/Rac1, we produced a hit list of potential regulators of kalirin activity suitable for follow-up analysis in
well-characterized and optimized assays. We hypothesize that small-molecule compounds isolated in HTS and
in silico screens modulate kalirin's GEF and biological activity in rodent and human iPSC-derived neuron
models, and reverse neuroarchitectural abnormalities in models of NPDs. We will test this hypothesis in the
following aims: 1) Hit validation and in vitro characterization, selection, and prioritization. 2) Prioritization of
mouse and human neuronal model systems for testing validated hits. 3) Characterization of validated hit
compounds in mouse and iPSC models.

## Key facts

- **NIH application ID:** 10173123
- **Project number:** 2R56MH071316-16
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peter Penzes
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $782,079
- **Award type:** 2
- **Project period:** 2005-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173123

## Citation

> US National Institutes of Health, RePORTER application 10173123, Small GTPase signaling in dendrites and spines (2R56MH071316-16). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10173123. Licensed CC0.

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