Authentic role of ATP signaling in micturition reflex

Abstract

Adenosine triphosphate (ATP) is a signaling molecule that regulates cellular processes. Based on previous studies of bladder function over the past decade, bladder ATP signaling was thought to have an essential role in the normal micturition reflex. In this study, we performed detailed analyses of bladder function in purinergic receptor-deficient mice using the automated voided stain on paper method and video-urodynamics. Unexpectedly, a lack of P2X2 or P2X3 receptors did not affect bladder function under normal physiological conditions, indicating that bladder ATP signaling is not essential for normal micturition reflex. In contrast, we found that lipopolysaccharide (LPS) induced markedly high levels of ATP release from the urothelium. In addition, LPS-induced rapid bladder hyperactivity was attenuated in P2X2−/− and P2X3−/− mice. Contrary to the previous interpretation, our present findings indicate that bladder ATP signaling has a fundamental role in the micturition reflex, especially in bladder dysfunction, under pathological conditions. Therefore, the bladder ATP signaling pathway might be a highly promising therapeutic target for functional bladder disorders. This study newly defines an authentic role for bladder ATP signaling in the micturition reflex.

Urothelial ATP signaling: what is its role in bladder sensation?

“…In addition, Kullmann et al and Yeh et al showed that intravesical administration of purinergic receptor antagonists improves bladder hyperactivity caused by intravesical administration of a muscarinic acetylcholine receptor agonist and by H 2 O 2 in rats, respectively. Furthermore, others found that intravesical administration of a purinergic receptor antagonist reduced bladder hyperactivity caused by intravesical instillation of lipopolysaccharide in mice . These findings demonstrate an important role of urothelial ATP signaling in bladder hyperactivity in pathological states.…”

“…Consequently, it has been generally believed that urothelial ATP signaling is essential for the normal micturition reflex; that is stretch‐induced urothelial ATP release activates bladder afferent nerves via P2X2, P2X3, and/or P2X2/3 receptors to mediate the sensation of bladder filling . However, recent evidence obtained from genetically modified mice has suggested the possibility that this prevailing concept should be further explored …”

“…Bladder afferent nerves, which project into the suburothelial layer of the bladder, express purinergic P2X2, P2X3, and/or P2X2/3 receptors. Pharmacological blockade and genomic deletion of P2X2, P2X3, and/or P2X2/3 receptors have been reported to ameliorate bladder dysfunction in various animal models of bladder disease . Therefore, the inhibition of these purinergic receptors on bladder afferent nerves might be clinically effective for the treatment of symptoms in IC, PBS, and OAB.…”

“…Recently, however, this long‐held urothelial ATP signaling theory was questioned by several studies using novel methodology. These studies have provided important insight into urothelial ATP signaling and have suggested that it is not essential for the micturition reflex under physiological conditions …”

Extracellular adenosine 5’-triphosphate concentrations changes in rat spinal cord associated with the activation of urinary bladder afferents. A microdialysis study

“…(15) However, recent experiments conducted in genetically engineered mice that do not express P 2 X 2 or P 2 X 3 receptors showed that these receptors are not essential for the normal micturition reflex. (16) …”