TRPV4 receptor as a functional sensory molecule in bladder urothelium: Stretch‐independent, tissue‐specific actions and pathological implications

The newly-recognised sensory role of bladder urothelium has generated intense interest in identifying its novel sensory molecules. Sensory receptor TRPV4 may serve such function. However, specific and physiologically-relevant tissue actions of TRPV4, stretch-independent responses, and underlying mechanisms are unknown and its role in human conditions has not been examined. Here we showed TRPV4 expression in guinea-pig urothelium, suburothelium and bladder smooth muscle, with urothelial predominance. Selective TRPV4 activation without stretch evoked significant ATP release – key urothelial sensory process, from live mucosa tissue, full thickness bladder but not smooth muscle, and sustained muscle contractions. ATP release was mediated by Ca2+-dependent, pannexin/connexin-conductive pathway involving protein tyrosine kinase, but independent from vesicular transport and chloride channels. TRPV4 activation generated greater Ca2+ rise than purinergic activation in urothelial cells. There was intrinsic TRPV4 activity without exogeneous stimulus, causing ATP release. TRPV4 contributed to 50% stretch-induced ATP release. TRPV4 activation also triggered superoxide release. TRPV4 expression was increased with aging. Human bladder mucosa presented similarities to guinea-pigs. Overactive bladders exhibited greater TRPV4- induced ATP release with age-dependence. These data provide the first evidence in humans for the key functional role of TRPV4 in urothelium with specific mechanisms and identify TRPV4 upregulation in aging and overactive bladders.