Purinergic signalling in the lower urinary tract

Abstract

The aim of this review is to describe the conceptual steps contributing to our current knowledge of purinergic signalling and to consider its involvement in the physiology and pathophysiology of the lower urinary tract. The voiding reflex involves ATP released as a cotransmitter with acetylcholine from parasympathetic nerves supplying the bladder and ATP released from urothelial cells during bladder distension to initiate the voiding reflex via P2X3 receptors on suburothelial low threshold sensory nerve fibres. This mechanosensory transduction pathway also participates, via high threshold sensory nerve fibres, in the initiation of pain in bladder and ureter. Treatment of prostate and bladder cancer with ATP is effective against the primary tumours in animal models and human cell lines, via P2X5 and P2X7 receptors, and also improves the systemic symptoms associated with advanced malignancy. Acupuncture is widely used for the treatment of urinary disorders, and a purinergic hypothesis is discussed for the underlying mechanism.

Neural Control of the Lower Urinary Tract

“…Adenosine triphosphate (ATP) is the excitatory transmitter mediating the noncholinergic contractions (15, 17, 87, 515). ATP excites the bladder smooth muscle by acting on P2X receptors which are ligand gated ion channels.…”

“…ATP excites the bladder smooth muscle by acting on P2X receptors which are ligand gated ion channels. Among the seven types of P2X receptors expressed in the bladder, P2X1 is the major subtype in the rat and human bladder smooth muscle (87, 515). Purinergic transmission has an important excitatory role in animal bladders but is not important in the normal human bladder.…”

“…Purinergic transmission has an important excitatory role in animal bladders but is not important in the normal human bladder. However, it appears to be involved in bladders from patients with pathological conditions such as detrusor overactivity (DO), chronic urethral outlet obstruction, or interstitial cystitis (87, 494). …”

“…When urothelial cells are activated via these receptors/ion channels in response to mechanical or chemical stimuli, they can in turn release chemical mediators such as NO, ATP, acetylcholine, prostaglandins, and substance P (50,53,54,86,87,109,213). These agents are known to have excitatory and inhibitory actions on afferent nerves, which are located close to or in the urothelium (16, 57).…”

Receptors, channels, and signalling in the urothelial sensory system in the bladder

“…A variety of signalling molecules (such as neurotrophins, neuropeptides, ATP, acetylcholine, prostaglandins, prostacyclin, nitric oxide and cytokines) are secreted by the urothelium 2,24,36,42 and it is able to communicate, possibly in a reciprocal manner, with other cell types including bladder nerves, smooth muscle cells, interstitial cells and inflammatory cells 2,27 . ATP seems to be the main messenger released from urothelial cells during purinergic mechanosensory transduction that acts on P2X 3 receptors on sensory nerves to generate signals that indicate bladder fullness, and pain 17,43 (FIG.…”