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Mechanisms of Disease: role of purinergic signaling in the pathophysiology of bladder dysfunction

Abstract

Although the 'purinergic nerve hypothesis' proposed by Burnstock in the early 1970s was met with considerable skepticism, it is now accepted that certain neurons use a purine nucleotide or nucleoside such as ATP or adenosine as a neurotransmitter. Likewise, early studies indicated that the human bladder is devoid of purinergic nerves mediating contraction; however, later studies demonstrated that purinergic nerve-mediated bladder contraction is increased in pathologic conditions such as interstitial cystitis. Cloning and sequencing studies have revealed four subtypes of adenosine receptors and eight subtypes of P2Y receptors, all of which are G-protein-coupled receptors. There are no reports of the cellular location of these receptors in the human bladder. P2X receptors are ligand-gated ion channels, and seven subunits have been cloned and sequenced. Immunohistochemical studies have determined that P2X1,2,4 subunits are on detrusor-muscle cells, P2X1–3,5 subunits are on bladder nerves and P2X2,3,5 subunits are on bladder urothelial cells. Development of purinergic antagonist drugs with selectivity for P2X1 receptors on detrusor muscle cells might be useful for treatment of detrusor overactivity. Antagonists with selectivity for P2X3 receptors on bladder sensory nerves might be clinically beneficial for treatment of urinary urgency, and perhaps chronic pelvic pain.

Key Points

  • Decreased ecto-ATPase in unstable bladders leading to an increased contractile effect of released ATP might be a mechanism of bladder instability in some patients

  • Between 50 and 80 years of age there is an age-associated increase in purinergic-mediated bladder contraction and ATP release and a decrease in cholinergic-mediated bladder contractions and acetylcholine release, which might be one of the mechanisms for the increased incidence of detrusor overactivity in the elderly

  • The functional purinergic receptors on bladder smooth-muscle cells that mediate contraction are either P2X1/P2X2 heteromultimers or P2X1, P2X2 and/or P2X4 homomultimers; development of antagonists to these P2X receptors is likely to be clinically useful in treatment of detrusor overactivity

  • Results from knockout-mice models indicate that the purinergic receptor that mediates bladder sensation and nociception is either a P2X3 homomultimer or a heteromultimer predominantly containing the P2X3 subunit; development of antagonists to this P2X receptor is likely to be clinically useful in the treatment of bladder overactivity, urgency and perhaps even chronic pelvic pain syndromes

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Correspondence to Michael R Ruggieri Sr.

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Ruggieri, M. Mechanisms of Disease: role of purinergic signaling in the pathophysiology of bladder dysfunction. Nat Rev Urol 3, 206–215 (2006). https://doi.org/10.1038/ncpuro0456

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