Abstract
Connexin43 (Cx43), the main gap junction and hemichannel forming protein in the urinary bladder, participates in the regulation of bladder motor and sensory functions and has been reported as an important modulator of day–night variations in functional bladder capacity. However, because Cx43 is expressed throughout the bladder, the actual role played by the detrusor and the urothelial Cx43 is still unknown. For this purpose, we generated urothelium-specific Cx43 knockout (uCx43KO) mice using Cre-LoxP system. We evaluated the day–night micturition pattern and the urothelial Cx43 hemichannel function of the uCx43KO mice by measuring luminal ATP release after bladder distention. In wild-type (WT) mice, distention-induced ATP release was elevated, and functional bladder capacity was decreased in the animals’ active phase (nighttime) when Cx43 expression was also high compared to levels measured in the sleep phase (daytime). These day–night differences in urothelial ATP release and functional bladder capacity were attenuated in uCx43KO mice that, in the active phase, displayed lower ATP release and higher functional bladder capacity than WT mice. These findings indicate that urothelial Cx43 mediated ATP signaling and coordination of urothelial activity are essential for proper perception and regulation of responses to bladder distension in the animals’ awake, active phase.
Highlights
Gap junction channels and hemichannels play an essential role in the maintenance of cell homeostasis and the coordination of cellular activity in various organ systems [1].Gap junctions, which are intercellular channels formed by the pairing and the docking of hemichannels from adjacent cells, provide a direct cytosol-to-cytosol pathway for exchange of ions and small molecules that couple the cells both electrically and metabolically
In contrast to what was observed in the urothelium of control mice, the intensity of Cx43 staining in the urothelium of urothelium-specific Cx43 knockout (uCx43KO) mice was clearly reduced, especially in the basal and the intermediate layers (Figure 1A)
The level of Cx43 expression was decreased in the urothelium of the uCx43KO mice, whereas in the suburothelium/detrusor muscle and in the liver, it was similar to those detected in control mice (Figure 1B)
Summary
Gap junction channels and hemichannels play an essential role in the maintenance of cell homeostasis and the coordination of cellular activity in various organ systems [1]. We demonstrate that urothelium-specific Cx43 downregulation blunts the day–night differences in the urothelial ATP release response to bladder distension and disrupts the diurnal regulation of bladder capacity in the awake, active phase of the uCx43KO mice. The relevance of these findings is discussed in the overall context of mechanisms and molecular mediators of bladder function, and we highlight the significance and the potential role of urothelial Cx43 in bladder physiology
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