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PIEZO2 in sensory neurons and urothelial cells coordinates urination


Henry Miller stated that “to relieve a full bladder is one of the great human joys”. Urination is critically important in health and ailments of the lower urinary tract cause high pathological burden. Although there have been advances in understanding the central circuitry in the brain that facilitates urination1,2,3, there is a lack of in-depth mechanistic insight into the process. In addition to central control, micturition reflexes that govern urination are all initiated by peripheral mechanical stimuli such as bladder stretch and urethral flow4. The mechanotransduction molecules and cell types that function as the primary stretch and pressure detectors in the urinary tract mostly remain unknown. Here we identify expression of the mechanosensitive ion channel PIEZO2 in lower urinary tract tissues, where it is required for low-threshold bladder-stretch sensing and urethral micturition reflexes. We show that PIEZO2 acts as a sensor in both the bladder urothelium and innervating sensory neurons. Humans and mice lacking functional PIEZO2 have impaired bladder control, and humans lacking functional PIEZO2 report deficient bladder-filling sensation. This study identifies PIEZO2 as a key mechanosensor in urinary function. These findings set the foundation for future work to identify the interactions between urothelial cells and sensory neurons that control urination.

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Fig. 1: Urinary dysfunction in individuals deficient in PIEZO2.
Fig. 2: Piezo2 is expressed in the lower urinary tract, and sensory neurons require PIEZO2 to detect low-pressure bladder filling.
Fig. 3: PIEZO2 is required for efficient micturition reflexes.
Fig. 4: PIEZO2 functions in both bladder urothelium and sensory neurons.

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Data availability

The raw data that support the findings of this study are available from the corresponding authors upon reasonable request.

Code availability

Code for calcium imaging analysis is previously published13. MATLAB (v.2018b) code used for cystometry analysis is available at


  1. de Groat, W. C. & Yoshimura, N. Afferent nerve regulation of bladder function in health and disease. Handb. Exp. Pharmacol. 194, 91–138 (2009).

    Article  Google Scholar 

  2. Keller, J. A. et al. Voluntary urination control by brainstem neurons that relax the urethral sphincter. Nat. Neurosci. 21, 1229–1238 (2018).

    Article  CAS  Google Scholar 

  3. Hou, X. H. et al. Central control circuit for context-dependent micturition. Cell 167, 73–86 (2016).

    Article  CAS  Google Scholar 

  4. Garry, R. C., Roberts, T. D. & Todd, J. K. Reflex responses of the external urethral sphincter of the cat to filling of the bladder. J. Physiol. 139, 13–14 (1957).

    CAS  PubMed  Google Scholar 

  5. Cockayne, D. A. et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407, 1011–1015 (2000).

    Article  ADS  CAS  Google Scholar 

  6. Andersson, K. E., Gratzke, C. & Hedlund, P. The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. BJU Int. 106, 1114–1127 (2010).

    Article  CAS  Google Scholar 

  7. Mochizuki, T. et al. The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J. Biol. Chem. 284, 21257–21264 (2009).

    Article  CAS  Google Scholar 

  8. Merrill, L., Gonzalez, E. J., Girard, B. M. & Vizzard, M. A. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat. Rev. Urol. 13, 193–204 (2016).

    Article  CAS  Google Scholar 

  9. Apodaca, G., Balestreire, E. & Birder, L. A. The uroepithelial-associated sensory web. Kidney Int. 72, 1057–1064 (2007).

    Article  CAS  Google Scholar 

  10. Zagorodnyuk, V. P., Brookes, S. J., Spencer, N. J. & Gregory, S. Mechanotransduction and chemosensitivity of two major classes of bladder afferents with endings in the vicinity to the urothelium. J. Physiol. 587, 3523–3538 (2009).

    Article  CAS  Google Scholar 

  11. Murthy, S. E. et al. The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci. Transl. Med. 10, (2018).

  12. Ranade, S. S. et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014).

    Article  ADS  CAS  Google Scholar 

  13. Szczot, M. et al. PIEZO2 mediates injury-induced tactile pain in mice and humans. Sci. Transl. Med. 10, (2018).

  14. Woo, S. H. et al. Piezo2 is the principal mechanotransduction channel for proprioception. Nat. Neurosci. 18, 1756–1762 (2015).

    Article  CAS  Google Scholar 

  15. Woo, S. H. et al. Piezo2 is required for Merkel-cell mechanotransduction. Nature 509, 622–626 (2014).

    Article  ADS  CAS  Google Scholar 

  16. Chesler, A. T. et al. The role of PIEZO2 in human mechanosensation. N. Engl. J. Med. 375, 1355–1364 (2016).

    Article  CAS  Google Scholar 

  17. Nonomura, K. et al. Piezo2 senses airway stretch and mediates lung inflation-induced apnoea. Nature 541, 176–181 (2017).

    Article  ADS  CAS  Google Scholar 

  18. Zeng, W. Z. et al. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 362, 464–467 (2018).

    Article  ADS  CAS  Google Scholar 

  19. Afshar, K., Mirbagheri, A., Scott, H. & MacNeily, A. E. Development of a symptom score for dysfunctional elimination syndrome. J. Urol. 182, 1939–1944 (2009).

    Article  Google Scholar 

  20. Ehrhardt, A. et al. Urinary retention, incontinence, and dysregulation of muscarinic receptors in male mice lacking Mras. PLoS ONE 10, e0141493 (2015).

    Article  Google Scholar 

  21. Flum, A. S. et al. Testosterone modifies alterations to detrusor muscle after partial bladder outlet obstruction in juvenile mice. Front Pediatr. 5, 132 (2017).

    Article  Google Scholar 

  22. Takezawa, K. et al. Authentic role of ATP signaling in micturition reflex. Sci. Rep. 6, 19585 (2016).

    Article  ADS  CAS  Google Scholar 

  23. Takezawa, K., Kondo, M., Nonomura, N. & Shimada, S. Urothelial ATP signaling: what is its role in bladder sensation? Neurourol. Urodyn. 36, 966–972 (2017).

    Article  CAS  Google Scholar 

  24. Ferguson, D. R., Kennedy, I. & Burton, T. J. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes–a possible sensory mechanism? J. Physiol. 505, 503–511 (1997).

    Article  CAS  Google Scholar 

  25. Agarwal, N., Offermanns, S. & Kuner, R. Conditional gene deletion in primary nociceptive neurons of trigeminal ganglia and dorsal root ganglia. Genesis 38, 122–129 (2004).

    Article  CAS  Google Scholar 

  26. Sengupta, J. N. & Gebhart, G. F. Mechanosensitive properties of pelvic nerve afferent fibers innervating the urinary bladder of the rat. J. Neurophysiol. 72, 2420–2430 (1994).

    Article  CAS  Google Scholar 

  27. Miyamoto, T. et al. Functional role for Piezo1 in stretch-evoked Ca2+ influx and ATP release in urothelial cell cultures. J. Biol. Chem. 289, 16565–16575 (2014).

    Article  CAS  Google Scholar 

  28. Maksimovic, S. et al. Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature 509, 617–621 (2014).

    Article  ADS  CAS  Google Scholar 

  29. Alcaino, C. et al. A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release. Proc. Natl Acad. Sci. USA 115, E7632–E7641 (2018).

    Article  CAS  Google Scholar 

  30. Wang, E. C. et al. ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells. J. Clin. Invest. 115, 2412–2422 (2005).

    Article  CAS  Google Scholar 

  31. Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).

    Article  ADS  CAS  Google Scholar 

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We thank D. Barucha-Goebel, A. R. Foley and S. Donkervoort for help with the clinical assessments; G. Averion, C. Jones and K. Brooks for experimental assistance; S. Ma and S. Simpson-Dworschak for early work on the project; E. Lacefield for helpful discussions; and the Scripps Histology Core for sample preparation. This work was supported by the Howard Hughes Medical Institute; the NIH grants R35 NS105067 to A.P., F32 DK121494 to K.L.M. and R01 NS108439 to L.S.; and the NIH Intramural Research Program funding from the National Center for Complementary and Integrative Health (A.T.C.) and from the National Institute of Neurological Disorders and Stroke (A.T.C. and C.G.B.).

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Authors and Affiliations



K.L.M. designed and performed all mouse cystometry, behavioural experiments and tissue histology, analysed data and, together with A.P., wrote the manuscript. D.S., T.O., C.G.B. and A.T.C. designed and performed the human clinical assessments. Calcium imaging and analysis was performed by N.G., K.L.M. and M.S. Retrograde labelling and FISH experiments were performed by K.L.M., A.M.C. and I.D. J.K. and L.T.S. contributed analytical tools for data analysis, technical support and conceptual project design. C.G.B, A.T.C. and A.P. contributed to project design and supervision. All authors discussed results and contributed to manuscript editing.

Corresponding authors

Correspondence to Alexander T. Chesler or Ardem Patapoutian.

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The authors declare no competing interests.

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Peer review information Nature thanks Eric Honoré, Jon Levine and Mark Nelson for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 The bladder urothelium expresses multiple mechanosensitive proteins, and PIEZO2 is not required for sensory neuron pinch responses.

a, FISH in bladder tissue with probes against Krt20 (green) and Piezo1 (white). DAPI in blue. b, FISH in bladder tissue with probes against Krt20 (green) and Tmem63b (white). DAPI in blue. c, Z-projection of the standard deviation of responses from genital pinch in WT and d, Piezo2cKO DRG. e, Quantification of peak responses during pinch shown as percent of baseline (each data point is one cell). n = 3 DRGs, 40 cells for WT, 4 DRGs and 69 cells for Piezo2cKO DRGs.

Extended Data Fig. 2 PIEZO2 is required for efficient micturition reflexes in male mice.

a, Hoxb8-cre;Ai9 bladder tissue, fixed, frozen and mounted to show tdTomato (red) throughout the tissue, labelled with DAPI (blue). Scale is 100 μm. Expression was evaluated in two mice. b, Example pressure and urethra activity traces from three wild-type males and c, three Hoxb8-cre;Piezo2fl/fl knockout male littermates. d, Heat map of individual bladder contraction events in wild-type and e, knockout male mice, with corresponding urethra activity below in f and g respectively. h, Bladder contraction intervals for males. i, Bladder pressures five seconds before peak contraction for males. Note: 1,200 s was the length of one recording. These dots represent recording periods in which the animal had no successful urination events. j, Total bladder pressure for males and k, sum of urethra activity during bladder contractions. n = 6 males per group. P < 0.0001 for graphs in h, i, j and k, two-sided Student’s t-test with Welch’s correction. l, Body weights from a subset of mice whose bladder weights are shown in Fig. 2t, and m, bladder weights from animals in l, shown as a percentage of body weight. Red horizontal lines indicate means, vertical red bars indicate +/− standard deviation (shown where possible).

Extended Data Fig. 3 Upk2- and Scn10a-cre expression and bladder weights.

a, Upk2-cre;Ai9 bladder tissue fixed, frozen and mounted to show tdTomato (red) throughout the urothelium, labelled with DAPI (blue). Expression was evaluated in two mice. b, Scn10a-cre;Ai9 bladder tissue fixed, frozen and mounted to show tdTomato (red) is not present. Expression was evaluated in two mice. Thin cryosections made neuronal endings difficult to visualize. Scale: 200 μm, applies to a and b. c, Scn10a-cre;Ai9 DRG tissue showing tdTomato (red) in the majority of neurons, and d, a cell backlabelled with CTB-Alexa 488 injected into bladder. e, Merge of c and d, DAPI in blue. 9/9 backlabelled bladder cells analysed from two mice were tdTomato positive. f, Quantification of freshly excised bladder weights from four Upk2-cre;Piezo2fl/fl knockout and wild-type littermates. Age-matched littermates were 10–11 months old, which could account for greater variability. g, Bladder weights from age-matched Scn10a-cre;Piezo2fl/fl knockout mice and wild-type littermates, 7–8 months old. Red lines indicate mean values.

Supplementary information

Supplementary Table 1

Clinical assessments and notes for all Piezo2-deficient patients interviewed. These represent the answers given by patients during clinician interviews, which sometimes differed from the patient’s own answers to the questionnaire (Table 1). Patient numbers correspond to the numbers shown in Table 1. Not all patients returned the questionnaire.

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Marshall, K.L., Saade, D., Ghitani, N. et al. PIEZO2 in sensory neurons and urothelial cells coordinates urination. Nature 588, 290–295 (2020).

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