Abstract
Pirt is a transmembrane protein predominantly expressed in peripheral neurons. However, the physiological and pathological roles of Pirt in hollow viscus are largely unknown. Here we show that Pirt deficiency in mice causes bladder overactivity. The density of α,β-meATP-induced currents is significantly reinforced in Pirt-deficient dorsal root ganglion (DRG) neurons. Pirt and P2X3 receptor co-localize in bladder nerve fibres and heterologous Pirt expression significantly reduces P2X3-mediated currents. Pirt interacts with P2X3 through the N-terminal 14 amino-acid residues. TAT-conjugated Pirt(N14) peptide (Pirt(N14)) is sufficient to inhibit P2X3 activation in bladder DRG neurons and to alleviate bladder overactivity in Pirt(-/-) mice. Pirt expression is decreased in the bladder of cyclophosphamide (CYP)-treated mice, a commonly used model of bladder overactivity. Importantly, Pirt(N14) administration reduces the frequency of bladder voiding and restores the voided volume of CYP-treated mice. Therefore, our results demonstrate that Pirt is an endogenous regulator of P2X3 in bladder function.
Highlights
Pirt is a transmembrane protein predominantly expressed in peripheral neurons
We demonstrate that Pirt regulates bladder voiding via the inhibition of purinergic receptor P2X3 and that a peptide derived from Pirt has inhibiting effects on bladder overactivity
These fibres express many receptors that respond to various mediators released during inflammation, injury and ischaemia from a number of cell types[22]
Summary
Pirt is a transmembrane protein predominantly expressed in peripheral neurons. the physiological and pathological roles of Pirt in hollow viscus are largely unknown. Pirt expression is decreased in the bladder of cyclophosphamide (CYP)-treated mice, a commonly used model of bladder overactivity. In response to physical and chemical stimulation, the urothelium releases several substances, including acetylcholine, ATP, prostaglandins and so on[6,7,8] These chemical agents modify afferent nerve activity and sensation in the suburothelial layer and in the muscle layer[2]. P2X3-null mice exhibit a marked urinary bladder hyporeflexia characterized by decreased voiding frequency and increased bladder capacity[11]. These reports suggest that the P2X3 receptors of afferent nerves play a crucial role in bladder control. We demonstrate that Pirt regulates bladder voiding via the inhibition of purinergic receptor P2X3 and that a peptide derived from Pirt has inhibiting effects on bladder overactivity
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