The regulation of distention-induced ATP release from urothelium by the adenylyl cyclase-cyclic AMP pathway

Abstract

Distention of the bladder during urine storage induces ATP release from urothelium, thereby facilitating transmission of visceral sensory signals to afferent nerve fibers. An excess of urothelial ATP release was found in interstitial cystitis, a condition accompanied by hyperesthesia of the urinary bladder; it remains unclear which signals are involved in this upregulation. The present study demonstrated that the adenylyl cyclase pathway enhances distention-induced ATP release in mouse bladder. In the absence of distention, adenylyl cyclase activation by forskolin or cyclic AMP increases by rolipram did not induce significant ATP release. However, forskolin or rolipram significantly enhanced ATP release from urothelium by a physiologically normal urine storage pressure (5 cmH 2 O). Blockade of adenylyl cyclases did not alter pressure-induced ATP release in normal condition. Thus, the adenylyl cyclase-cAMP pathway might be activated in pathological conditions and cause an excess of ATP release.Recent studies revealed that urinary bladder epithelium (urothelium) functions as a visceral sensory organ as well as a barrier against urine (1, 3, 6). Distention of the bladder wall during urine storage causes a release of adenosine triphosphate (ATP) from the urothelium. Released ATP could act through the purinergic receptor P2X 3 , which is expressed on afferent nerve terminals in close proximity to urothelial cells. Studies using P2X 3 -deficient mice revealed that P2X 3 is essential for control of the urinary bladder volume reflex (11, 32); the pain response behavior was also reduced in these mice (11). These studies indicate that urothelial ATP release could play a key role in both volume-and noxious stimulus-evoked reflexes. In fact, an excess of urothelial ATP release was detected in interstitial cystitis or overactive bladder, conditions accompanied by visceral hyperesthesia leading to frequent urination or bladder pain (2, 28-30). However, the precise signaling cascade involved in the pathological increase of urothelial ATP release remains unknown. Identification of this signaling cascade may lead to improved strategies for clinical management of storage symptoms or bladder pain. Urothelial ATP release is mediated by various signal transduction pathways (24). In these, Ca 2+ plays an important role in the induction or regulation of ATP release. Urothelial ATP release was shown to be triggered by activation of transient receptor potential (TRP) V1 or TRPV4 (4,22,25), which are ion channels permeable to cations such as Ca 2+ . Knockout mice lacking TRPV1 or TRPV4 showed impairment of stretch-evoked increases in intracellular Ca 2+ and in ATP release from the urothelium (4, 15). Furthermore, Ca 2+ release from the endoplasmic reticulum (ER) is involved in induction of urothelial ATP release (23). On the other hand, store-operated Ca 2+ entry, which is driven by depletion of Ca 2+ stores in the ER, exerted an opposite, suppressive effect (23). Involvement of Ca 2+ implies that ATP

Receptor GPR91 contributes to voiding function and detrusor relaxation mediated by succinate

“…Urothelial cyclic AMP is involved in the afferent component of micturition by facilitating ATP release, which in turn activates bladder reflexes and enhances bladder sensation, particularly under pathological conditions. ATP is known to play a major role in the afferent sensory component of the voiding cycle by binding to its receptor P2X3 21 . The reduced intracellular and extracellular contents of ATP in urothelial cells incubated with succinate, as demonstrated in this study, might explain at least in part the relaxation observed.…”

<b>ATP release from bladder urothelium and serosa in a rat model of partial bladder outlet </b><b>obstruction </b>

“…The present study demonstrated that pBOO increases al change caused by pBOO released ATP from serosal side of the bladder. The release of ATP from the urothelium upon physical distention is a well-known occurrence (22,23). In our study, the change in the ATP increment caused by physical distention (10 and 30 cmH 2 O) was not significant between the control and pBOO rat urothelium.…”

“…ATP is released from the pelvic postganglionic nerve ending with acetylcholine and activates the P2Y receptors in the bladder smooth muscle to lead the initial bladder contraction in the process of micturition (3,6,21). ATP is also released from urothelial cells during bladder stretching (2,8,29) or upon activation of the transient receptor potential (TRP) V1 channel, muscarinic acetylcholine receptors, or 5HT receptors, and activates P2X receptors on the afferent nerve terminals (2,23). These P2X receptors can elicit the activity of the afferent nerves during the storage of urine and most likely trigger the micturition reflex (28).…”

“…ATP release assay using the Ussing chamber. ATP release assay was performed as described previously (22,23). In brief, the isolated urinary bladders were opened vertically from the urethra to the apex.…”

Regulatory Effects of 5-Hydroxytryptamine Receptors on Voiding Function

“…The inhibitory effect of 5-HT 1D on ATP release could be achieved by suppressing cAMP, because the adenylyl cyclase-cAMP pathway facilitates distention-evoked ATP release from the urothelium [41]. These data suggest that urothelial 5-HT 1D could inhibit the micturition reflex by depressing ATP release.…”