Mechanisms of disease: role of purinergic signaling in the pathophysiology of bladder dysfunction.

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 P2X(1,2,4) subunits are on detrusor-muscle cells, P2X(1-3,5) subunits are on bladder nerves and P2X(2,3,5) subunits are on bladder urothelial cells. Development of purinergic antagonist drugs with selectivity for P2X(1) receptors on detrusor muscle cells might be useful for treatment of detrusor overactivity. Antagonists with selectivity for P2X(3) receptors on bladder sensory nerves might be clinically beneficial for treatment of urinary urgency, and perhaps chronic pelvic pain.