Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3

Gao, Xianhua; Feng, Ji Feng; Wang, Wei; Xiang, Zhen; Liu, Xiu Jie; Zhu, Changliang; Tang, Zongxi; Dong, Xiangyang; He, Cheng

doi:10.1038/ncomms8650

Cited by 18 publications

(18 citation statements)

References 37 publications

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“…TRPM8 channel currents that were induced by menthol and cool temperatures were significantly reduced in the Pirt -/-DRG neurons. Pirt also inhibits purinergic receptor P2X3 and reduces bladder overactivity [12] , but unlike the Pirt positive regulation of TRPV1, this inhibitory effect is mediated through the interaction between the Pirt N-terminal and P2X3 [12] . Pirt promotes TRPM8 channel activity [11] , but the underlying …”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide interacting regulator of TRP (Pirt) enhances TRPM8 channel activity in vitro via increasing channel conductance

Tang

Dong

et al. 2015

Acta Pharmacol Sin

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Aim: Pirt is a two-transmembrane domain protein that regulates the function of a variety of ion channels. Our previous study indicated that Pirt acts as a positive endogenous regulator of the TRPM8 channel. The aim of this study was to investigate the mechanism underlying the regulation of TRPM8 channel by Pirt. Methods: HEK293 cells were transfected with TRPM8+Pirt or TRPM8 alone. Menthol (1 mmol/L) was applied through perfusion to induce TRPM8-mediated voltage-dependent currents, which were recorded using a whole-cell recording technique. PIP2 (10 μmol/L) was added into the electrode pipettes (PI was taken as a control). Additionally, cell-attached single-channel recordings were conducted in CHO cells transfected with TRPM8+Pirt or TRPM8 alone, and menthol (1 mmol/L) was added into the pipette solution. Results: Either co-transfection with Pirt or intracellular application of PIP2 (but not PI) significantly enhanced menthol-induced TRPM8 currents. Furthermore, Pirt and PIP2 synergistically modulated menthol-induced TRPM8 currents. Single-channel recordings revealed that co-transfection with Pirt significantly increased the single channel conductance. Conclusion: Pirt and PIP2 synergistically enhance TRPM8 channel activity, and Pirt regulates TRPM8 channel activity by increasing the single channel conductance.

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Section: Introductionmentioning

confidence: 99%

Phosphoinositide interacting regulator of TRP (Pirt) enhances TRPM8 channel activity in vitro via increasing channel conductance

Tang

Dong

et al. 2015

Acta Pharmacol Sin

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“…A recent report described that CPP derived from the tat domain of HIV(17) improves delivery of therapeutic proteins and nucleic acids to the bladder. (8, 9) Moreover, the ability of other CPPs to bind bladder urothelium has been reported. (10, 11)…”

Section: Discussionmentioning

confidence: 99%

“…(8–11) In the majority of these studies, the tests were performed on bladders with intact mucosa, which is contrary to clinical presentations in which the urothelium layer is rarely intact as a result of underlying pathological processes and treatments. For instance, during trans-urethral resection (TUR) of non-invasive bladder carcinoma in situ (CIS),(12) the urothelium layer is scratched off together with the cancerous lesion, exposing lamina propria.…”

Section: Introductionmentioning

confidence: 99%

Cell-penetrating peptide CGKRK mediates efficient and widespread targeting of bladder mucosa following focal injury

Griffin

Cheng

Hayashi

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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The bladder presents an attractive target for topical drug delivery. The barrier function of the bladder mucosa (urothelium) presents a penetration challenge for small molecules and nanoparticles. We found that focal mechanical injury of the urothelium greatly enhances the binding and penetration of intravesically-administered cell-penetrating peptide CGKRK (Cys-Gly-Lys-Arg-Lys). Notably, the CGKRK bound to the entire urothelium, and the peptide was able to penetrate into the muscular layer. This phenomenon was not dependent on intravesical bleeding and was not caused by an inflammatory response. CGKRK also efficiently penetrated the urothelium after disruption of the mucosa with ethanol, suggesting that loss of barrier function is a prerequisite for widespread binding and penetration. We further demonstrate that the ability of CGKRK to efficiently bind and penetrate the urothelium can be applied towards mucosal targeting of CGKRK-conjugated nanogels to enable efficient and widespread delivery of a model payload (rhodamine) to the bladder mucosa.

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“…Pirt has a role in detecting cold via regulating the function of TRPM8 [18]. In our recent work, Pirt was found to reduce bladder overactivity by inhibiting P2X3 receptors in bladder nerve fibers [19], which led to the current study of the potential relationship between Pirt and the P2X2 receptor subtype.…”

Section: Introductionmentioning

confidence: 93%

Co-localization of Pirt protein and P2X2 receptors in the mouse enteric nervous system

Guo

Sui

Gao

et al. 2016

Purinergic Signalling

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P2X2 receptors, with other P2X receptor subtypes, have an important role mediating synaptic transmission in regulating the functions of the gastrointestinal tract. Our recent work has found a new regulator of P2X receptor function, called phosphoinositide-interacting regulator of transient receptor potential channels (Pirt). In the present work, we have shown that Pirt immunoreactivity was localized in nerve cell bodies and nerve fibers in the myenteric plexus of the stomach, ileum, proximal, and distal colon and in the submucosal plexus of the jejunum, ileum, proximal, and distal colon. Almost all the Pirt-immunoreactive (ir) neurons were also P2X2-ir, and co-immunoprecipitation experiments have shown that Pirt co-precipitated with the anti-P2X2 antibody. This work provides detailed information about the expression of Pirt in the gut and its co-localization with P2X2, indicating its potential role in influencing P2X2 receptor function.

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Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3

Cited by 18 publications

References 37 publications

Phosphoinositide interacting regulator of TRP (Pirt) enhances TRPM8 channel activity in vitro via increasing channel conductance

Phosphoinositide interacting regulator of TRP (Pirt) enhances TRPM8 channel activity in vitro via increasing channel conductance

Cell-penetrating peptide CGKRK mediates efficient and widespread targeting of bladder mucosa following focal injury

Co-localization of Pirt protein and P2X2 receptors in the mouse enteric nervous system

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