# Underlying mechanisms controlling urothelial ATP release and their contributions to urinary bladder physiology and pathophysiology

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $352,125

## Abstract

Project Summary
 ATP was first discovered to be released from the urinary bladder epithelium (urothelium) in response to
bladder distension in 1997. In the years since, many studies have determined additional stimuli that result in
ATP release, however relatively few studies have examined the mechanism(s) of this release. As it is
commonly thought that urinary ATP plays a significant role in the sensory pathways that control micturition, a
deeper understanding of urothelial ATP release is essential for understanding urinary bladder
physiology/pathology.
 We have recently discovered two distinct mechanisms controlling ATP release from the urothelium. The
first involved pannexin hemi-channels, a type of large-pore ion channel permeable to ATP. We believe that this
mechanism plays a significant role in the physiological control of micturition, as pharmacological inhibition or
genetic knockdown of pannexin channels causes a marked inhibition of reflex bladder activity in the rat. The
second mechanism involves secretory lysosomes. We have evidence that this mechanism plays a role in the
emergence of bladder inflammation, as lysosomal exocytosis can be stimulated by bacterial endotoxins. This
has led us to hypothesize that the ATP released through different mechanisms may have separate
physiological effects.
 The next step into fully understanding ATP's role in bladder physiology and pathology is to fully
characterize the intracellular signaling pathways responsible for activating or inhibiting either release
mechanism. To that end, we propose to use known activators of either pannexin mediated release (bladder
distension, α3 nicotinic receptor stimulation and P2Y6 purinergic receptor stimulation) or lysosomal mediated
release (toll-like receptor stimulation) to examine common intracellular signaling pathways that may control
release. For example, it is already known that pannexin mediated release is dependent on intracellular calcium
signaling and activation of the RhoA/ROCK pathway. Our current research aims to determine if each stimulus
(mechanical stretch, activation of an ion channel and activation of a metabotropic receptor) feeds into these
known intracellular pathways. We will also examine how release of lysosomal calcium following NAADP
signaling or alterations in lysosomal pH, pathways known to modulate lysosomal exocytosis in other tissues,
alter lysosomal release of ATP from the urothelium. Finally, we will characterize how the two ATP release
mechanisms interact, as we have previously demonstrated that inhibition of pannexin-mediated release
potentiated lysosomal release, suggesting a crosstalk between release mechanisms. It is our hope that this
project will lead to a more complete understanding of the mechanisms controlling purinergic signaling in the
urinary bladder and lead to more effective treatments for bladder pathology.

## Key facts

- **NIH application ID:** 9957065
- **Project number:** 5R01DK117884-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JONATHAN M BECKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,125
- **Award type:** 5
- **Project period:** 2018-08-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957065

## Citation

> US National Institutes of Health, RePORTER application 9957065, Underlying mechanisms controlling urothelial ATP release and their contributions to urinary bladder physiology and pathophysiology (5R01DK117884-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957065. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*