# Molecular mechanisms of Kv1 channel localization at the axon initial segment

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

PROJECT SUMMARY
As the site of action potential initiation, the axon initial segment (AIS) contains high densities of voltage-gated
sodium (Nav) and potassium (Kv) channels that generate and shape the action potential. Kv1 channels are a
prominent type of ion channel at the AIS that modulate action potential waveform. Despite their functional
importance, the mechanisms responsible for the localization of these channels at the AIS are poorly understood.
In contrast, the recruitment of other ion channels to the AIS is well established and depends on interaction with
the AIS scaffold protein, AnkyrinG (AnkG). Nav1 and Kv7 channels directly interact with AnkG through a
conserved binding motif that Kv1 channels lack. However, unlike Nav1 and Kv7 channels, Kv1 channels contain
PDZ binding motifs, which permit interactions with PDZ domain containing proteins. Kv1 channels have been
shown to interact with the PDZ domain-containing scaffold protein PSD93 that is highly enriched at the AIS.
Although in vitro knockdown studies found that PSD93 is required for Kv1 channel clustering at the AIS,
subsequent in vivo knockout studies demonstrated that PSD93 is dispensable, suggesting that other
mechanisms can cluster Kv1 channels at the AIS. Previous work also suggests that AnkG is required for AIS Kv1
channel clustering, but the link between AnkG and Kv1 channels is unknown and may be indirect. Thus, the
mechanisms underlying Kv1 channel localization at the AIS are unclear. Our lab recently identified a new AIS
scaffold protein, SCRIB, that directly binds AnkG. SCRIB contains multiple PDZ domains and may constitute a
novel mechanism for clustering Kv1 channels at the AIS. However, the function of SCRIB at the AIS has not
been investigated. The objective of this proposal is to define the molecular mechanisms responsible for clustering
Kv1 channels at the AIS. Aim 1 will use AAV- and CRISPR-based knockouts, conditional knockout mouse
models, and immunostaining to determine if SCRIB, PSD93, and AnkG are necessary for AIS Kv1 channel
clustering in vitro and in vivo. Aim 2 will use co-immunoprecipitations and surface clustering assays in
heterologous cells to determine the molecular interactions between Kv1 channels and the AIS scaffold proteins
SCRIB, PSD93, and AnkG. The proposed experiments will establish a model for how Kv1 channels are localized
at the AIS. The Rasband lab has extensive experience elucidating the molecular mechanisms underlying AIS
assembly. Thus, the proposed experiments are designed to take advantage of this expertise and the many tools
and reagents available in the Rasband lab. This research project will also provide a robust training experience
for my development as a molecular neurobiologist. Through the completion of the proposed aims, I will advance
the research skills, critical thinking skills, scientific communication skills, and mentorship skills that I will need for
my future career as an independent investigator.

## Key facts

- **NIH application ID:** 10995127
- **Project number:** 1F31NS139435-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Victoria Palfini
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-03 → 2027-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995127

## Citation

> US National Institutes of Health, RePORTER application 10995127, Molecular mechanisms of Kv1 channel localization at the axon initial segment (1F31NS139435-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10995127. Licensed CC0.

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