# Synaptic function of BK channel-interacting proteins

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2024 · $551,722

## Abstract

The BK channel (also known as Slo1) is almost ubiquitously expressed in the body with many important
physiological functions, such as regulating neurotransmitter release by acting at presynaptic sites of neurons.
Mutations of the channel may cause diverse diseases. Physiological functions of Slo1 depend to great degrees
on its expression level in the cell membrane and interactions with regulatory proteins. Genetic screen for mutants
that suppress a sluggish phenotype caused by a hyperactive Slo1 in C. elegans led to the identification of two
proteins required for Slo1 physiological functions in vivo, including a melatonin receptor and an ubiquitin E3
ligase. Electrophysiological and behavioral analyses indicate that Slo1 mediates melatonin’s sleep-promoting
effect in worms, and that Slo1’s physiological roles in regulating neurotransmitter release and sleep depend on
melatonin secretion and activation of the melatonin receptor. In a heterologous expression, human Slo1 is
activated by melatonin through the MT1 but not MT2 melatonin receptor. However, it remains to be determined
where Slo1 acts in the nervous system to regulate sleep in worms, and whether mammalian Slo1 in native
neurons may be also activated by melatonin through a specific melatonin receptor. Mass spectrometry analyses
identified a protein greatly increased in mutants of the E3 ligase compared with wild type. Mutations of the gene
encoding this protein led to increased Slo1 function, suggesting that it is a novel inhibitory regulator of Slo1, and
that the E3 ligase regulates Slo1 by facilitating degradation of this putative inhibitory regulator. Further studies
are needed to define a molecular pathway through which the E3 ligase regulates Slo1. This project is to
investigate 1) how the E3 ligase regulates Slo1 through the inhibitory regulator and other proteins; 2) where and
how Slo1 acts in the nervous system to regulate sleep in C. elegans; and 3) why MT1 but not MT2 may allow
Slo1 activation by melatonin in the heterologous expression system, and whether melatonin can also regulate
Slo1 in mouse brain through MT1 but not MT2. We will answer these questions using a combination of
electrophysiological, genetic, cellular, and molecular biological approaches. Results of the proposed studies are
expected to produce important new knowledge about how Slo1 interacts with other proteins to regulate cellular
excitability, neurotransmitter release, and behavior.

## Key facts

- **NIH application ID:** 10754569
- **Project number:** 5R01MH085927-13
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** ZHAO-WEN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $551,722
- **Award type:** 5
- **Project period:** 2009-12-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754569

## Citation

> US National Institutes of Health, RePORTER application 10754569, Synaptic function of BK channel-interacting proteins (5R01MH085927-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10754569. Licensed CC0.

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