The Pannexin 1 Channel and the P2X7 Receptor Are in Complex Interplay to Regulate the Release of Soluble Ectonucleotidases in the Murine Bladder Lamina Propria.
The Pannexin 1 Channel and the P2X7 Receptor Are in Complex Interplay to Regulate the Release of Soluble Ectonucleotidases in the Murine Bladder Lamina Propria.
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DOI：
10.3390/ijms24129964
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发表时间：
2023-06-09
影响因子：
5.6
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中科院分区：
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膀胱尿道括约肌在充盈过程中向固有层（LP）释放ATP，其可激活传入神经元上的P2 X受体并触发排尿反射。有效的ATP浓度在很大程度上取决于膜结合和可溶性外核苷酸酶（s-ENTDs）的代谢，后者以机械敏感的方式在LP中释放。Pannexin 1（PANX 1）通道和P2 X7受体（P2 X7 R）参与尿路上皮ATP的释放，并且在物理和功能上是偶联的，因此我们研究它们是否调节s-ENTDs的释放。使用超灵敏的HPLC-FLD，我们评估了1，N6-乙烯基-ATP（eATP，底物）降解为eADP，eAMP和e-腺苷（e-ADO）在腔外溶液中，在填充过程中与小鼠逼尿肌游离膀胱的LP接触，然后加入底物，作为s-ENERGY释放的间接测量。Panx 1的缺失增加了扩张诱导的s-ENTDs的释放，但不是自发的，而BzATP或高浓度的ATP在WT膀胱中激活P2 X7 R增加了两者。然而，在用PANX 1抑制肽10 Panx处理的Panx 1 −/−膀胱或WT膀胱中，BzATP对s-ENTDS释放没有影响，表明P2 X7 R活性依赖于PANX 1通道开放。因此，我们的结论是，P2 X7 R和PANX 1是在复杂的相互作用，以调节s-ENTDs的释放和维持适当的ATP浓度的LP。因此，虽然牵张激活的PANX 1阻碍s-ENTDS释放，可能在膀胱充盈结束时保持有效的ATP浓度，但P2 X7 R激活（可能在膀胱炎中）将促进s-ENTDS介导的ATP降解，以抵消过度的膀胱兴奋性。
The bladder urothelium releases ATP into the lamina propria (LP) during filling, which can activate P2X receptors on afferent neurons and trigger the micturition reflex. Effective ATP concentrations are largely dependent on metabolism by membrane-bound and soluble ectonucleotidases (s-ENTDs), and the latter are released in the LP in a mechanosensitive manner. Pannexin 1 (PANX1) channel and P2X7 receptor (P2X7R) participate in urothelial ATP release and are physically and functionally coupled, hence we investigated whether they modulate s-ENTDs release. Using ultrasensitive HPLC-FLD, we evaluated the degradation of 1,N6-etheno-ATP (eATP, substrate) to eADP, eAMP, and e-adenosine (e-ADO) in extraluminal solutions that were in contact with the LP of mouse detrusor-free bladders during filling prior to substrate addition, as an indirect measure of s-ENDTS release. Deletion of Panx1 increased the distention-induced, but not the spontaneous, release of s-ENTDs, whereas activation of P2X7R by BzATP or high concentration of ATP in WT bladders increased both. In Panx1−/− bladders or WT bladders treated with the PANX1 inhibitory peptide 10Panx, however, BzATP had no effect on s-ENTDS release, suggesting that P2X7R activity depends on PANX1 channel opening. We concluded, therefore, that P2X7R and PANX1 are in complex interaction to regulate s-ENTDs release and maintain suitable ATP concentrations in the LP. Thus, while stretch-activated PANX1 hinders s-ENTDS release possibly to preserve effective ATP concentration at the end of bladder filling, P2X7R activation, presumably in cystitis, would facilitate s-ENTDs-mediated ATP degradation to counteract excessive bladder excitability.
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