# GABA activation of the M-current

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $337,969

## Abstract

Pentameric ligand-gated ion channels (LGICs) are activated by neurotransmitter binding to highly specialized,
inter-subunit, extracellular binding pockets. In contrast, voltage-gated potassium (Kv) channels are activated by
membrane depolarization, electromechanically communicated by the voltage sensor to the pore module. Kv
channels composed of KCNQ2/3 heteromers generate the neuronal M-current, a ubiquitous and essential
hyperpolarizing K+ current controlling excitability in mammalian CNS. This proposal is based on our recent
discovery that KCNQ2/3 channels are directly activated by γ-aminobutyric acid (GABA), the primary inhibitory
neurotransmitter in vertebrate CNS, with sensitivity comparable to that of the most sensitive α/β/γ GABAA
receptor LGICs. In contrast, the excitatory neurotransmitter glutamate, which is structurally related to GABA,
has no effect on KCNQ2/3 activity. We have identified the KCNQ2/3 GABA binding site as KCNQ3-W265, and
find the position is highly conserved in deuterostome clades, present in some Cnidarians, but absent in
protostomes; it is also absent from cardiac-expressed KCNQ1. In addition, we have found that GABA analogs
and metabolites exhibit similar structure-activity relationships (SARs) for KCNQ2/3 channel activation and
anticonvulsant activity. The metabolites include β-hydroxybutyrate (BHB), the primary ketone body produced in
response to fasting or ketogenic diets, which protect against seizures. We find that BHB is a potent KCNQ2/3
activator and anticonvulsant, uncovering a molecular target for the therapeutic effects of ketosis. Our findings
show that despite their wide structural disparity, GABA activates both principal classes of inhibitory ion
channels in vertebrate neurons, creating a new paradigm for regulation of Kv channel gating and inhibitory
neurotransmission. We propose three Specific Aims directed towards a fuller understanding of the
mechanisms, breadth and scope underlying this novel signaling modality. In Aim 1 we will elucidate the
molecular requirements for GABA and BHB regulation of KCNQ channels and when this capability evolved. In
Aim 2 we will define the KCNQ binding sites of key GABA analogs and metabolites we recently discovered to
also activate KCNQs, and leverage synergy between these compounds to develop optimized, potent
anticonvulsants. In Aim 3, we will utilize newly CRISPR-Cas9 generated mice bearing germline mutations in
the KCNQ3 & 5 GABA/BHB binding sites to determine the importance and KCNQ isoform-dependence of the
anticonvulsant actions of BHB and the ketogenic diet. We will then use cellular electrophysiological analysis to
quantify the age- and KCNQ-isoform dependence of GABA and BHB modulation of native M-current and
neuronal excitability. The project will thoroughly define the fundamental aspects of a novel, unexpected form
of inhibitory neuronal signaling, with the dual goals of understanding its role in brain physiology and harnessing
the knowledge to help devel...

## Key facts

- **NIH application ID:** 10084328
- **Project number:** 5R01NS107671-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Geoffrey W Abbott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $337,969
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084328

## Citation

> US National Institutes of Health, RePORTER application 10084328, GABA activation of the M-current (5R01NS107671-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10084328. Licensed CC0.

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