# Modulation of Ca2+ -activated K+ channels by CFTR Correctors

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $612,703

## Abstract

Cystic fibrosis (CF) results from mutations in the CFTR Cl- channel resulting in diminished transepithelial Cl-
secretion. The most common CFTR mutation, F508del, results in a channel that fails to correctly fold/traffic.
Thus, compounds were sought to improve the folding/trafficking of this misfolded CFTR - referred to as
correctors. Vertex pioneered the identification of CFTR correctors, and in 2019 introduced Trikafta, consisting of
the correctors, VX-661 (Tezacafor) and VX-445 (Elexacaftor), together with the CFTR potentiator VX-770
(Ivacaftor). This highly effective modulator therapy (HEMT) has proved to be highly efficacious. Unfortunately,
real-world studies have reported adverse events (AE) in a subset of CF patients taking these HEMT, including
headache, hypertension and mental health issues, such as anxiety, low mood, insomnia and “brain fog”. The
mechanisms by which HEMT induce these AE remain unknown and thus represent a critical gap in our
understanding of drug action. Herein, we demonstrate the CFTR corrector VX-445 (Elexacaftor) inhibits the
intermediate (KCa3.1) conductance, Ca2+-activated K+ channel (KCa), resulting in an inhibition of Cl- secretion
across WT and F508del CFTR-expressing primary human bronchial epithelial cells (HBEs). Further, we
demonstrate these CFTR correctors potentiate the large (BKCa; KCa1.1) conductance KCa. As KCa channels
are widely expressed, including in neurons, where they control neuronal excitability, and vascular smooth
muscle, where they regulate vascular reactivity, understanding how CFTR correctors modulate KCa activity is
crucial to understanding these AE. Thus, the rationale for our studies is by defining the mechanisms by which
CFTR correctorsinhibit KCa3.1 and potentiate BKCa channels, and how this affectsthe physiology of cells where
these channels are expressed, we will better understand the AE induced by HEMT. Based on this, we propose
the following aims: (1) Define the mechanism(s) by which CFTR correctors inhibit KCa3.1 and KCa2.x channels
and the effects on HBE function. (2) Define the mechanism by which CFTR correctors potentiate BKCa channels
and the effects on HBE function. (3) Define the effects of CFTR corrector-mediated KCa3.1/KCa2.x inhibition
and BKCa potentiation on vascular reactivity and neuronal action potential firing. To carry out these studies, we
will utilize a combination of in vitro and ex vivo techniques, including electrophysiological, molecular, protein
biochemical, live-cell fluorescence imaging, as well as wire- and pressure-myography on mouse aortic rings and
microvascular arteries, and patch-clampingon primary cultures of cortical and hippocampal neurons. Our studies
will be the first to demonstrate CFTR correctors directly inhibit KCa2.x/KCa3.1 and potentiate BKCa channels and
how this affects ion transport across HBEs, vascular reactivity and neuronal action potential firing. As HEMT
represent the standard of care for CF patients it is highly significant to u...

## Key facts

- **NIH application ID:** 10980161
- **Project number:** 1R01HL171413-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** DANIEL C DEVOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $612,703
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980161

## Citation

> US National Institutes of Health, RePORTER application 10980161, Modulation of Ca2+ -activated K+ channels by CFTR Correctors (1R01HL171413-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10980161. Licensed CC0.

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