# Mechanism of BK Channel Gating

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $715,791

## Abstract

Our long-term goal is to understand the molecular mechanisms of BK channel activation. BK-type K+
channels are activated by voltage and intracellular Ca2+. These channels are important in modulating muscle
contraction, neural transmission and circadian pacemaker output, and have been shown to associate with
hypertension, schizophrenia, epilepsy and paroxysmal dyskinesia. These channels are being pursued as
therapeutic targets for neuronal ischemia, trauma and cognitive decline. The voltage sensor and Ca2+ binding
sites in BK channels have been identified. However, the structural basis for the coupling between sensors and
the activation gate, which are located in different structural domains, still remains elusive. A central question in
this crucial step of BK channel gating is how these different structural domains interact with one another to
mediate the coupling between the sensors and the activation gate. This proposal is motivated by the long-
awaited and recently solved atomic structures of a whole BK channel. These structures offer new insights on
fundamental mechanisms of sensor-pore coupling that may differ from the previous understanding. The
structure and functional studies lead to a general hypothesis for answering this question: interactions among
the voltage sensor domain (VSD), the cytosolic domain (CTD), and the pore-gate domain (PGD) all contribute
to the sensor-pore coupling. We propose three specific aims to examine three key aspects of this hypothesis:
1) the VSD-PGD interactions in VSD-pore coupling, 2) the VSD-CTD interactions in both VSD-pore and Ca2+-
pore couplings, and 3) the role of a peptide linker between PGD and CTD in both the VSD-pore and Ca2+-pore
couplings. We will use novel structure based screening methods to identify compounds that modulate channel
function. These compounds and mutations in the channel protein will serve as probes to indicate the structural
motifs that are key to the sensor-pore coupling in BK channels. Threading the biophysics of mutations and
modulators onto the channel structures will allow us to understand the molecular mechanisms of how
physiological stimuli open BK channels. The results of these studies will identify novel binding sites, chemical
cores and new mechanisms of altering channel function by drugs, which will directly help drug development
targeting BK channels. Our studies on BK channels may provide insights for the understanding of other ion
channels that share similar structural and functional characteristics.

## Key facts

- **NIH application ID:** 10018643
- **Project number:** 5R01HL142301-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JONATHAN R SILVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $715,791
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018643

## Citation

> US National Institutes of Health, RePORTER application 10018643, Mechanism of BK Channel Gating (5R01HL142301-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018643. Licensed CC0.

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