# Pore Gating Mechanisms of BK Channels

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $420,402

## Abstract

Large-conductance, calcium- and voltage-activated potassium (BK) channels play a variety of physiologically
important roles, are innovative drug targets for disorders of almost every organ system, and possess
biophysical features that make them an ideal system for studying allosteric mechanisms of channel function
(gating) by voltage and ligands and modulation by drugs. The BK channel is a unique member of the
potassium channel family, characterized by exceptionally large single-channel conductance and dual activation
by two physiological signals, membrane voltage and intracellular free calcium. A variety of experimental
evidence indicates that BK channels lack the intracellular bundle-crossing gate that is present in many other
potassium channels. Thus the opening and closing of the BK channel pore during activation must be
controlled by other mechanisms. Recent determination of the 3D structure of the complete BK channel from
Aplysia californica at a near-atomic resolution provides a new structural basis for understanding these
mechanisms. The structures not only confirm that the lack of a bundle-crossing gate, but suggest novel
mechanisms of BK channel activation mediated by state-dependent interaction among amino acids in the deep
pore and selectivity filter regions. We hypothesize that the BK channel activation gate is located within the
selectivity filter and/or deep-pore. We have made progress towards testing this hypothesis by establishing
methods to determine the relationship between activation and selectivity filter inactivation and analyzing the
structure-function relationship of BK channel pore residues. With the newly available structural information and
novel tools that we have developed, including concatenated tandem subunit constructs to restrict mutations to
individual BK channel subunits within the tetrameric channel, we are now poised to determine the pore gate
localization and central channel pore gating mechanisms. We propose to pursue the following three specific
aims to elucidate the pore-gating mechanisms of BK channels: 1) determine the properties and mechanisms of
selectivity filter gating in BK channels; 2) determine the role of the deep-pore residues and their interactions in
BK channel gating; and 3) define the location of the activation and inactivation gates by determining the state-
dependent accessibility of the selectivity filter and deep pore to Cys-modifying reagents. Overall, the proposed
research is designed to investigate systematically the central pore-gating mechanisms of BK channels. The
findings from the proposed studies will deepen our understanding of molecular mechanisms of BK channel
activation by voltage and calcium and facilitate development of novel therapeutic reagents targeting BK
channels for the treatment or prevention of neurobiological, cardiovascular, and other types of disorders and
diseases.

## Key facts

- **NIH application ID:** 9916769
- **Project number:** 5R01GM127332-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Richard Aldrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,402
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916769

## Citation

> US National Institutes of Health, RePORTER application 9916769, Pore Gating Mechanisms of BK Channels (5R01GM127332-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9916769. Licensed CC0.

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