Based on these roles, the Panx1 channel can be viewed as one of the molecular components of the bladder mechanosensory and transduction systems and, as such, is expected to play key roles in the regulation of bladder function. Our view of the role played by the urothelium in bladder function changed radically over the last fifteen years since the demonstration by Ferguson and colleagues that distension of the bladder wall, as occurs during bladder filling with urine, induces release of significant amounts of ATP from the urothelium. This finding led to the proposal that besides acting as a selective barrier that separates and protects the bladder from the urine contents, the urothelium also functions as a sensor for changes in intravesical pressure. Several studies have since been conducted to identify the molecular mediators and mechanisms involved in urothelial mechanotransduction and ATP release. In this study we provide evidence that the Panx1 channel is one of these molecular mediators. We show that Panx1 channels are expressed throughout the bladder mucosa and in TRT-HU1 immortalized human urothelial cells, and that ATP release in response to bladder wall distension and mechanical stimulation of TRT-HU1 cells is inhibited by the Panx1 channel blocker mefloquine and is blunted in Panx1 deficient mice. The characteristic Silmitasertib mechanosensitivity and the large size and permeability of the pore formed by the Panx1 channel make this channel an ideal candidate for a role in the urothelial mechanosensory and transduction systems. In other cells that are also naturally subjected to mechanical stimulation, such as erythrocytes, airway epithelial cells and bone cells, Panx1 channels have also been shown to provide a mechanosensitive pathway for ATP release and dye-uptake. Besides responding to cell surface deformation, Panx1 channels can also be activated by cellular depolarization, increase in intracellular Ca2+ and extracellular K+ and have been shown to be the “large permeation pore” recruited by P2X7R activation. The precise mechanisms whereby P2X7R activates the Panx1 channel are still unknown, but there is evidence that a tyrosine kinase of the Src family participates in the initial events leading to Panx1 channel opening following P2X7R stimulation. This sensitivity of Panx1 channels to P2X7R stimulation creates a peculiar situation in which activation of either one can result in the activation or enhanced activation of the other, triggering a cycle of reciprocal activation where ATP release induces further ATP release. Such a mechanism may have dire consequences and lead to cell death when it is not controlled. In this regard, observations that extracellular ATP can inhibit Panx1 channels suggest that an autoregulatory mechanism may modulate P2X7R-Panx1 activation and control ATP-induced ATP release. The relevance of this functional interplay between Panx1 channels and P2X7R is becoming increasingly apparent. For example, activation of the P2X7R-Panx1 complex has been proposed to modulate the range of intercellular signaling in the astrocytic network, has been implicated in processing and release of interleukin-1b, and to mediate inflammationinduced enteric neuron death. This functional interplay between P2X7R and Panx1 seems to be broadly observed.