Role of ecto-5'-nucleotidase in bladder function activity and smooth muscle contractility

The purinergic system regulates bladder function through the action of ATP and its active metabolites. This signalling mechanism involves ATP, ADP and adenosine binding to specific receptors, including purine-gated cation channels (P2X1-7) and various G protein coupled receptors (nucleotides – P2Y1,2,4,6,11–14 and adenosine – A1, A2A, A2B, A3). The breakdown of purines is facilitated by enzymes, such as ectonucleoside triphosphate diphosphohydrolases (ENTPD1, 2, 3, 8), which convert ATP into ADP and then to AMP, and by ecto-5’-nucleotidase (NT5E) and urothelial alkaline phosphatase (ALPL), which convert AMP into adenosine. Dysfunction in ATP breakdown and signalling are linked to lower urinary tract symptoms in patients, affecting the contractility of detrusor smooth muscle through altered purinergic mechanisms [1, 2].

Previous animal studies suggest that the interplay between adenosine A2B receptors and nucleotide P2Y12 receptors, via ADP action, regulates bladder contractility. Knockout mice lacking P2y12 or Adora2b (A2bKO) gene expression exhibit opposing effects on bladder function parameters [3, 4]. Entpd1 knockout mice also show dysregulated bladder smooth muscle contractility due to abnormal purine kinetics, whilst bladders from Nt5e knockout (Nt5eKO) mice demonstrate altered responses to ADP stimulation [4].

In a recent study, Barge et al., (2024) investigated the role of NT5E in modulating detrusor smooth muscle contractility using Nt5eKO mice [5]. Various assays were used to confirm the absence of NT5E expression in mouse bladders, and bladder function and contractility were assessed. Nt5eKO mice displayed increased voiding frequency with reduced voiding intervals and decreased bladder compliance. This study highlights the involvement of NT5E in maintaining bladder function by modulating smooth muscle activity. The bladder abnormalities in Nt5eKO mice were milder than those seen in A2BKO mice and it has been proposed that the absence of NT5E might trigger compensatory mechanisms, including P2Y12 receptor downregulation and ALPL upregulation, to mitigate voiding dysfunction [3,4,5].