# BK channel regulation by auxiliary LRR proteins

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $350,000

## Abstract

PROJECT SUMMARY: Ion channel regulation by variable auxiliary subunits is a major mechanism in
generating diversity of ion channel function and thus variability in electrical signaling in different tissues and
cells. Large conductance, calcium- and voltage-activated potassium (BK) channels are ubiquitously expressed
and critically involved in various cellular and physiological processes including regulation of neuronal
excitability and synaptic transmission and control of contractile tone of almost all types of smooth muscle cells.
BK channels are diversified in structure and function by the presence of several tissue specific auxiliary β and 
subunits. Since our initial identification of the leucine-rich repeat containing (LRRC) membrane protein
LRRC26 as the BK channel auxiliary 1 subunit, an increasing number of LRRC proteins, among hundreds of
LRRC proteins in the human protein database, have been found to function as regulatory proteins of ion
channels. Currently, little is known about the mechanisms underlying ion channel regulation by most regulatory
LRRC proteins. The BK channel auxiliary 1 subunit have characteristics of an atypical “all-or-none”
modulatory action, an exceptionally large capability in affecting the BK channel’s voltage-gating, a predicted
major effect on the allosteric coupling between the voltage sensor activation and channel pore-opening, and a
competitive relationship with a small molecule BK channel activator mallotoxin (rottlerin). Based on our
previous and current studies, we hypothesize that the auxiliary 1 subunit modulates BK channels via a central
intramembrane mechanism and also subsidiary extracellular and intracellular mechanisms. To test our
hypothesis and elucidate the molecular mechanisms of BK channel modulation by auxiliary  subunits, we
propose to pursue the following 3 specific aims: 1) determine the molecular basis underlying an atypical “all-or-
none” action of the 1 subunit on BK channel modulation; 2) determine the molecular mechanisms of BK
channel modulation by the 1 subunit involving transmembrane domains; 3) determine the molecular
mechanisms of BK channel modulation by the 1 subunit and mallotoxin involving cytoplasmic domains. The
proposed research in this grant application is designed to systematically investigate the biochemical and
biophysical mechanisms governing BK channel regulation by the auxiliary 1 subunit and mallotoxin. The
knowledge obtained in this study could be applicable to ion channel regulation by other regulatory LRRC
proteins. The findings from the proposed studies will shed light on mechanisms of BK channel voltage gating
and provide in-depth understanding of the 1 subunit’s atypical “all-or-none” action and exceptional capability in
modulating BK channel voltage-gating. They will also help in creation of novel therapeutic reagents targeting
BK channels in treatment or prevention of neurobiological, cardiovascular, and other types of disorders and
diseases.

## Key facts

- **NIH application ID:** 10405072
- **Project number:** 5R01NS078152-10
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jiusheng Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $350,000
- **Award type:** 5
- **Project period:** 2012-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405072

## Citation

> US National Institutes of Health, RePORTER application 10405072, BK channel regulation by auxiliary LRR proteins (5R01NS078152-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10405072. Licensed CC0.

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