# Regulation of mechanosensitive K+ channels in detrusor smooth muscle by estrogen

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2022 · $421,040

## Abstract

Project Summary
The bladder must refrain from premature contraction during filling. This project investigates an intrinsic
mechanism of detrusor muscles in mouse and humans that senses volume changes through the elongation of
smooth muscle fibers. The mechanism is due to the expression and function of stretch-dependent K+ channels.
Previous studies have shown that stretch of detrusor smooth muscle cells (SMCs) activates outward current that
stabilizes the excitability of these cells. Blockers of the stretch-activated K+ channels cause significant activation
of transient contractions (TCs) in the bladder wall during filling, and TCs are a primary stimulant of sensory
information conveyed by pelvic afferents. We found that Kcnk2, which encodes the dominant stretch-dependent
conductance TREK1 in detrusor SMCs, is down-regulated after loss of female hormones following ovariectomy.
We noted a concomitant increase in TCs when TREK1 levels decreased. We also found that estrogen can
rescue nearly normal bladder function after ovariectomy. Such findings do not completely agree with the
literature regarding the effects of hormone replacement therapy on overactive bladder, and we will explore
possible reasons for this discrepancy. One explanation could be that the timing of estrogen replacement could
be critical for efficacy. Thus, we have proposed experiments to study the effects of the delay between
ovariectomy and estrogen replacement on the ability of estrogen to restore Kcnk2 and TREK1 expression and
normal bladder responses to filling. We have also found in preliminary experiments that there is a time-
dependent loss of estrogen receptor α (ERα) after ovariectomy. Thus, we will investigate the time-dependence
of the loss of estrogen receptors and the correlation between receptor loss and reduction in the effectiveness of
estrogen replacement. Another idea to be investigated is that the balance between ERα and ERβ might change
after ovariectomy, causing not only loss of effectiveness of estrogen replacement but also shifting the responses
to estrogen from helpful to eleterious to normal bladder function. This question will be explored using animals
with SMC-specific knockouts of ERα and ERβ. The project will use several state-of-the-art molecular and
physiological assays to provide rigorous associations between expression of TREK1 and possibly TREK2
channels and bladder function. The consequences of changes in ERα and ERβ expression and estrogen
regulation of Kcnk2 and Kcnk10 will provide new information about the role of stretch-dependent K+
conductances in bladder function and suggest a mechanism for the development of overactive bladder after
menopause.

## Key facts

- **NIH application ID:** 10457352
- **Project number:** 5R01DK119491-05
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** KENTON M SANDERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $421,040
- **Award type:** 5
- **Project period:** 2018-09-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457352

## Citation

> US National Institutes of Health, RePORTER application 10457352, Regulation of mechanosensitive K+ channels in detrusor smooth muscle by estrogen (5R01DK119491-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10457352. Licensed CC0.

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