SUFU 2019: Purinergic Receptors P2Y12 and A2B Antagonistically Regulate Bladder Function

Miami, FL (UroToday.com) The authors in this project hypothesized that purinergic P2Y12 and A2B receptors play an important role in regulating bladder contraction and relaxation through mediating extracellular ADP and adenosine signaling. They used control wild type, P2Y12KO, and A2BKO mice in C57BL/6J background. Bladder phenotyping was performed using voiding spot assay and cystometrogram. Contractility of bladder smooth muscle (BSM) strips were evaluated by myography in response to electrical field stimulation, combined with specific receptor agonists and antagonists, and further validated by calcium imaging on cultured BSM cells. Lastly, molecular and imaging approaches were used to study potential underlying mechanisms.

What they found that there was extensive evidence for the reciprocal interplay of multiple receptors responding to ATP, ADP and adenosine agonists which regulate bladder function significantly (figure). ADP stimulated P2Y12 receptors, causing BSM contraction, while adenosine signaling actively inhibited BSM purinergic contractility through A2B receptors. The modulation of adenylyl cyclase - cAMP signaling via A2B and P2Y12 interaction actively regulated bladder contractility by modulating intracellular calcium levels. Knockout mice lacking the receptors display diametrically opposed bladder phenotypes with P2Y12KOs exhibiting an underactive bladder phenotype with increased bladder capacity and reduced voiding frequency, while A2BKOs have overactive bladder with decreased capacity and increased voiding frequency. The opposing phenotypes in P2Y12KO and A2BKO mice not only resulted from dysregulated BSM contractility, but also from abnormal BSM cell growth. Finally, we demonstrate that intraperitoneal administration of drugs targeting P2Y12 or A2B receptor rescues these abnormal phenotypes in both knockouts.

At the end they concluded that P2Y12 or A2B receptor antagonistically modulate bladder capacity and voiding frequency through regulating downstream adenylyl cyclase - cAMP signaling pathway. These findings strongly indicate that P2Y12 and A2b receptors are attractive therapeutic targets for human patients with LUTS.

Figure 1. Interplay of P2Y12 and A2b signaling plays a key role in regulating BSM cell function and overall bladder activity.
UroToday_SUFU2019_PURINERGIC Receptors P2Y12 _1.png

UroToday_SUFU2019_PURINERGIC Receptors P2Y12 _1.png

Presented by: Weiqun Yu¹, MD, PhD, Assistant Professor of Medicine, Harvard Medical School, Boston, MA
Authors: Yuan Hao¹, Lu Wang¹, Huan Chen¹, Theodore Gartner², Warren Hill¹, Simon Robson¹, Mark Zeidel¹, Weiqun Yu¹
Author Affiliation:
1. Beth Israel Deaconess Medical Center,
2. University of Memphis

Written by: Bilal Farhan, MD, Clinical Instructor, Female Urology and Voiding Dysfunction, Department of Urology, University of California, Irvine @Bilalfarhan79 at the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction Winter Meeting, SUFU 2019, February 26 - March 2, 2019, Miami, Florida

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