Sensing the fullness of the bladder

Mechanosensory transduction participates in vital physiological functions such as control of blood pressure, food intake and micturition. Within the urinary tract, electrical impulses in bladder afferent fibres encode the fullness (volume and/or pressure) of the bladder; the information is conveyed via the pelvic and hypogastric nerves to the central neuronal circuits which in turn generate efferent nerve activity to drive coordinated activity of detrusor contraction and urethral sphincter relaxation that initiate evacuation (de Groat, 2006). Extensive efforts have been devoted in recent years to investigate the mechanisms that control bladder afferent activity in normal and in pathological conditions. Despite of the various progresses reported in the literature, the fundamental question of how mechanical force is transduced into afferent discharges remains largely unresolved. It has long been hypothesized that mechanosensory transduction relies on mechanically gated ion channels expressed on afferent terminals. Studies in C. elegans and Drosophila have identified three classes of putative mechanosensory transduction molecules: the degenerin/ENaC/ASIC channels, the transient receptor potential (TRP) cation channels and the two-pore-domain K+ channels (Chalfie, 2009). However, little information is currently available as to whether these channels, except for TRPV1 (Birder et al. 2002; Daly et al. 2007), participate in mechanosensory transduction in the urinary bladder. On the other hand, there has also been increasing interest in the putative sensory role of the urothelial (and other non-neuronal) cells, which have been shown to express a range of putative ‘sensory molecules’ and to release chemical mediators such as ATP, NO and prostanoids in response to mechanical and chemical stimulations (Birder, 2005). These mediators may in turn interact with receptors on afferent terminals to activate afferents or to modulate afferent excitability. In an article in this issue of The Journal of Physiology, Zagorodnyuk et al. (2009) employed a flat-sheet guinea pig bladder preparation to study the mechanosensory responses of bladder afferents by ‘close-to-target’ extracellular recordings. They had previously identified five major functional types of bladder afferents in this species (Zagorodnyuk et al. 2006, 2007) and here they focused on two types of bladder afferents with receptive fields in the vicinity of the urothelium. They examined the effects of degenerin/ENaC/ASIC channel blockers on the responses of muscular-mucosal and mucosal high-responding afferents to muscle stretch and/or mucosal stroking. Amiloride (100 μm) was ineffective, whilst remarkably, benzamil attenuated stretch- and/or stroking-induced afferent discharges in a concentration-dependent manner with 300 μm benzamil virtually abolishing stretch-induced responses. Stretch-activated channel blockers (gadolinium and SKF96365), on the other hand, were without effect on the mechanosensory responses. Furthermore, they showed that mechanosensory responses in these fibres were unaltered in the presence of a purinergic antagonist pyridoxal phosphate 6-azophenyl-2′,4′-disulfonic acid (PPADS) or when calcium-dependent vesicle release of chemical mediators was blocked. The authors concluded that mechanosensory transduction in muscle-mucosal and mucosal high-responding fibres does not rely on Ca2+-dependent vesicle release of chemical mediators such as ATP. Instead, benzamil-sensitive stretch-activated ion channels are likely to mediate mechanosensory transduction by receptive terminals. If they are right, these findings may represent an important step towards eventually delineating the molecular mechanisms of mechanosensory transduction in the urinary bladder. Conceivably, the search for mechanosensory transduction molecules can be narrowed down to the benzamil-sensitive degenerin/ENaC/ASIC channel family, some of which are known to be expressed in the urothelium, the detrusor muscle and the afferent terminals. Nevertheless, considering that relatively high concentrations of benzamil were needed to block the mechanosensory activity in the guinea pig bladder, further studies using more potent and selective pharmacological tools, with other species as well as transgenic animals, should be warranted. It may be worth pointing out that the finding that Ca2+ free perfusion did not affect mechanosensory activity in the guinea pig bladder does not necessarily preclude a sensory role of non-neuronal cells in other conditions. Rather, the data at best imply that non-neuronal release of mediators may not be sufficient to exert significant effects on afferent terminals in such experimental condition. Indeed, there has been plenty of experimental data indicating that the urothelial contribution to mechanosensory activity may be up-regulated in pathological conditions. Moreover, the use of Ca2+ free perfusion may not be sufficient to block potential intercellular communication between primary afferents and non-neuronal cells via exchange of second messenger molecules through gap junctions, as has been demonstrated by Ennes et al. (1999) for DRG and colonic myocytes co-cultured in vitro. An exciting new development in the field of mechanotransduction in vascular smooth muscles has been the findings that several Gq-coupled GPCRs can be activated by membrane stretch, leading to the activation of certain TRP channels via the phospholipase C (PLC) pathway (Voets & Nilius, 2009). It will be interesting to investigate whether a similar GPCR–TRP channel interaction mediates mechanosensory transduction in the urinary bladder.