# New approaches to understanding BK channelopathies at the molecular level of single channels

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $425,573

## Abstract

ABSTRACT
New approaches to understanding BK channelopathies at the molecular level of single channels.
Mutations in KCNMA1 BK potassium channels produce a wide range of channelopathies which include epilepsy,
dyskinesis, autism, multiple congenital abnormalities, intellectual disability, developmental delay, axial
hypotonia, ataxia, cerebral and cerebellar atrophy, bone thickening, tortuosity of arteries, malformation
syndrome, and others. We suggest that the majority of studies that seek to understand the biophysical basis of
these BK channelopathies have not been studying the predominant channels; we plan to do so. The majority of
these channelopathies arise in individuals who are heterozygous for the mutant gene. Since BK channels are
tetrameric, composed of four like subunits, mutant subunits could assemble with wild-type (WT) subunits to form
an ensemble of channels with different stoichiometries. The vast majority of the ensemble channels (88%) would
be heterotetrameric hybrid channels containing a varied number of mutant subunits (from one to three). However,
these hybrid channels are typically overlooked, and the mutations found in channelopathy patients have usually
been studied in the laboratory by expressing only the mutant subunit in a laboratory expression system.
Assuming random assembly of subunits, the purely mutant channels would not represent more than 6% of the
channels found in the cells of a heterozygous patient. Based on these incomplete studies many mutations were
categorized into gain-of-function (GOF) or loss-of-function (LOF) categories due to the findings of enhanced or
reduced activation of BK channels, respectively based on homotetrameric mutant channels. We suggest that the
omission of studying the full palette of channel types present in these patients has led to a chaotic and inaccurate
categorization of phenotypes by not recognizing that most aberrant channels in these patients may be hybrids
which constitute the majority of the aberrant channels in heterozygous channelopathies. In Aim 1 using a
combination of electrophysiological techniques including single channel analysis, we propose to show that a cell
carrying one mutant and one WT KCNMA1 allele expresses an ensemble of BK channels dominated by hybrid
channels assembled from both mutant and WT subunits. In Aim 2 we will determine the functional properties
and gating mechanisms to determine how the predominant channel forms associated with BK channelopathies
(as determined in Aim 1) alter channel activation. In Aim 3 we will test the hypothesis that some genetic variants
of BK channels result in a truncated subunit that leads to a reduced amount of BK current in cells when
heterozygous with WT subunits. Although these variant genes circulate in the population they are not reported
to cause neurological disease when heterozygous. Nevertheless, these mutations need to be studied because
reduced BK currents could confer a furtive genetic pre-disposition to neurol...

## Key facts

- **NIH application ID:** 10911038
- **Project number:** 5R01GM149998-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** KARL L MAGLEBY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $425,573
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911038

## Citation

> US National Institutes of Health, RePORTER application 10911038, New approaches to understanding BK channelopathies at the molecular level of single channels (5R01GM149998-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10911038. Licensed CC0.

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