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  • Review Article
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Receptors, channels, and signalling in the urothelial sensory system in the bladder

Nature Reviews Urology volume 13, pages 193–204 (2016)Cite this article

Subjects

Key Points

  • Complex neural pathways coordinate the activities of the urinary bladder. The bladder reflex exists in two modes of operation, storage and elimination. The elimination phase is triggered by urothelial mechanosensors

  • Urothelial cells exhibit specialized sensory and signalling properties enabling responses to stimuli and release of chemical mediators, and express diverse receptors and ion channels linked to mechanoceptive and nociceptive sensations

  • The urothelium secretes many signalling molecules (including neurotrophins, neuropeptides, acetylcholine, prostaglandins, nitric oxide, and cytokines); but ATP seems to be the main messenger in voiding reflexes and pain

  • Transient receptor potential (TRP) channels from different subfamilies are expressed in the bladder, exhibit specific distributions in the lower urinary tract, and are implicated in its normal and pathological physiology

  • The urothelium expresses purinergic receptors and releases neuroactive chemicals, including ATP, from its apical and basolateral surfaces in response to stimuli

  • Current research is focusing on the identification of novel targets in the sensory limb of the micturition reflex (such as TRP channels and purinergic neurotransmission) to treat sensory voiding disorders

Abstract

The storage and periodic elimination of urine, termed micturition, requires a complex neural control system to coordinate the activities of the urinary bladder, urethra, and urethral sphincters. At the level of the lumbosacral spinal cord, lower urinary tract reflex mechanisms are modulated by supraspinal controls with mechanosensory input from the urothelium, resulting in regulation of bladder contractile activity. The specific identity of the mechanical sensor is not yet known, but considerable interest exists in the contribution of transient receptor potential (TRP) channels to the mechanosensory functions of the urothelium. The sensory, transduction, and signalling properties of the urothelium can influence adjacent urinary bladder tissues including the suburothelial nerve plexus, interstitial cells of Cajal, and detrusor smooth muscle cells. Diverse stimuli, including those that activate TRP channels expressed by the urothelium, can influence urothelial release of chemical mediators (such as ATP). Changes to the urothelium are associated with a number of bladder pathologies that underlie urinary bladder dysfunction. Urothelial receptor and/or ion channel expression and the release of signalling molecules (such as ATP and nitric oxide) can be altered with bladder disease, neural injury, target organ inflammation, or psychogenic stress. Urothelial receptors and channels represent novel targets for potential therapies that are intended to modulate micturition function or bladder sensation.

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Figure 1: An overview of micturition reflex control and cell layers of the wall of the urinary bladder.
Figure 2: Illustration of low-level afferent nerve discharge that is present throughout bladder filling.
Figure 3: Hypothetical model of purinergic mechanosensory transduction and the involvement of TRP channels in the LUT focusing on potential interactions among bladder sensory nerves, urothelial cells, detrusor smooth muscle cells and ICC.

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Acknowledgements

The authors thank current and former members of the Vizzard laboratory who have contributed to the studies described within including: Lauren Arms, Mary Beth Klinger, Susan Malley, Abbey Peterson, Kimberly Corrow, Katarina Zvarova, Peter Zvara, Li-ya Qiao, and Bopaiah P. Cheppudira. Gratitude is expressed to Susan Malley for her assistance in creating the figures and table. Research from the Vizzard laboratory described herein was funded by the National Institutes of Health (NIH) grants DK051369 (M.A.V.), DK060481 (M.A.V.). Additional support was also provided by grants from the National Center for Research Resources (5 P30 RR 032135) and the National Institute of General Medical Sciences (8 P30 GM 103498) from the NIH.

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  1. Department of Neurological Sciences, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, 05405, Vermont, USA

    Liana Merrill, Eric J. Gonzalez, Beatrice M. Girard & Margaret A. Vizzard

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  1. Liana Merrill
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  2. Eric J. Gonzalez
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All authors researched data for the article, discussed content and reviewed the manuscript before submission. M.A.V., L.M. and E.J.G. wrote the article.

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Correspondence to Margaret A. Vizzard.

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M.A.V. is funded by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. The other authors declare no competing interests.

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Merrill, L., Gonzalez, E., Girard, B. et al. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol 13, 193–204 (2016). https://doi.org/10.1038/nrurol.2016.13

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