scholarly journals Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant

2016 ◽  
Vol 113 (17) ◽  
pp. E2363-E2372 ◽  
Author(s):  
Mahmud Arif Pavel ◽  
Caixia Lv ◽  
Courtney Ng ◽  
Lei Yang ◽  
Parul Kashyap ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Single Point ◽  
Receptor Potential ◽  
Cyst Formation ◽  
Activation Mechanism ◽  
Gain Of Function ◽  
Monovalent Ions

Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex. The activation mechanism of TRPP2 is unknown, which significantly limits the study of its function and regulation. Here, we generated a constitutively active gain-of-function (GOF) mutant of TRPP2 by applying a mutagenesis scan on the S4–S5 linker and the S5 transmembrane domain, and studied functional properties of the GOF TRPP2 channel. We found that extracellular divalent ions, including Ca2+, inhibit the permeation of monovalent ions by directly blocking the TRPP2 channel pore. We also found that D643, a negatively charged amino acid in the pore, is crucial for channel permeability. By introducing single-point ADPKD pathogenic mutations into the GOF TRPP2, we showed that different mutations could have completely different effects on channel activity. The in vivo function of the GOF TRPP2 was investigated in zebrafish embryos. The results indicate that, compared with wild type (WT), GOF TRPP2 more efficiently rescued morphological abnormalities, including curly tail and cyst formation in the pronephric kidney, caused by down-regulation of endogenous TRPP2 expression. Thus, we established a GOF TRPP2 channel that can serve as a powerful tool for studying the function and regulation of TRPP2. The GOF channel may also have potential application for developing new therapeutic strategies for ADPKD.

scholarly journals Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Qiang Liu ◽  
Jin Wang ◽  
Xin Wei ◽  
Juan Hu ◽  
Conghui Ping ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Epidermal Keratinocytes ◽  
Transient Receptor Potential Vanilloid ◽  
Growth Disorders ◽  
Open Probability ◽  
Gain Of Function ◽  
Sensory Channel

The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive updated therapeutics for skin inflammation.

scholarly journals The transient receptor potential A1 ion channel (TRPA1) modifies in vivo autonomous ureter peristalsis in rats

2020 ◽  
Author(s):  
Philipp Weinhold ◽  
Luca Villa ◽  
Frank Strittmatter ◽  
Christian Gratzke ◽  
Christian G. Stief ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential A1 ◽  
Transient Receptor

Role and activation mechanism of the Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel in mouse models of chronic pain

Neuropeptides ◽  
2017 ◽  
Vol 65 ◽  
pp. 130
Author(s):  
Zsuzsanna Helyes ◽  
Balint Scheich ◽  
Adam Horvath ◽  
Balint Botz ◽  
Valeria Tekus ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Ion Channel ◽  
Mouse Models ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Activation Mechanism ◽  
Transient Receptor

scholarly journals Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine

2020 ◽  
Author(s):  
Qiang Liu ◽  
Juan Hu ◽  
Jin Wang ◽  
Xin Wei ◽  
Conghui Ping ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Epidermal Keratinocytes ◽  
Transient Receptor Potential Vanilloid ◽  
Growth Disorders ◽  
Open Probability ◽  
Gain Of Function ◽  
Sensory Channel

AbstractThe multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is selectively targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular docking and mutagenesis, we further uncovered single residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive updated therapeutics for skin inflammation.

scholarly journals Electrophile-Induced Conformational Switch of the Human TRPA1 Ion Channel Detected by Mass Spectrometry

2020 ◽  
Vol 21 (18) ◽  
pp. 6667
Author(s):  
Lavanya Moparthi ◽  
Sven Kjellström ◽  
Per Kjellbom ◽  
Milos R. Filipovic ◽  
Peter M. Zygmunt ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ion Channel ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Receptor Potential ◽  
Full Length ◽  
Conformational Switch ◽  
Large N ◽  
Wide Range ◽  
Transient Receptor

The human Transient Receptor Potential A1 (hTRPA1) ion channel, also known as the wasabi receptor, acts as a biosensor of various potentially harmful stimuli. It is activated by a wide range of chemicals, including the electrophilic compound N-methylmaleimide (NMM), but the mechanism of activation is not fully understood. Here, we used mass spectrometry to map and quantify the covalent labeling in hTRPA1 at three different concentrations of NMM. A functional truncated version of hTRPA1 (Δ1-688 hTRPA1), lacking the large N-terminal ankyrin repeat domain (ARD), was also assessed in the same way. In the full length hTRPA1, the labeling of different cysteines ranged from nil up to 95% already at the lowest concentration of NMM, suggesting large differences in reactivity of the thiols. Most important, the labeling of some cysteine residues increased while others decreased with the concentration of NMM, both in the full length and the truncated protein. These findings indicate a conformational switch of the proteins, possibly associated with activation or desensitization of the ion channel. In addition, several lysines in the transmembrane domain and the proximal N-terminal region were labeled by NMM, raising the possibility that lysines are also key targets for electrophilic activation of hTRPA1.

Lutein Inhibits the Function of the Transient Receptor Potential A1 Ion Channel in Different In Vitro and In Vivo Models

2011 ◽  
Vol 46 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Györgyi Horváth ◽  
Éva Szőke ◽  
Ágnes Kemény ◽  
Teréz Bagoly ◽  
József Deli ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
In Vivo Models ◽  
Transient Receptor Potential A1 ◽  
Transient Receptor

scholarly journals Competitive Interactions between PIRT, the Cold Sensing Ion Channel TRPM8, and PIP2 Suggest a Mechanism for Regulation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nicholas J. Sisco ◽  
Cole V. M. Helsell ◽  
Wade D. Van Horn
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Receptor Potential ◽  
Binding Studies ◽  
Behavioral Studies ◽  
Regulatory Complex ◽  
Transient Receptor ◽  
Solution Nuclear Magnetic Resonance ◽  
Cold Sensing

Abstract TRPM8 is a member of the transient receptor potential ion channel family where it functions as a cold and pain sensor in humans and other higher organisms. Previous studies show that TRPM8 requires the signaling phosphoinositide lipid PIP2 to function. TRPM8 function is further regulated by other diverse mechanisms, including the small modulatory membrane protein PIRT (phosphoinositide regulator of TRP). Like TRPM8, PIRT also binds PIP2 and behavioral studies have shown that PIRT is required for normal TRPM8-mediated cold-sensing. To better understand the molecular mechanism of PIRT regulation of TRPM8, solution nuclear magnetic resonance (NMR) spectroscopy was used to assign the backbone resonances of full-length human PIRT and investigate the direct binding of PIRT to PIP2 and the human TRPM8 S1-S4 transmembrane domain. Microscale thermophoresis (MST) binding studies validate the NMR results and identify a competitive PIRT interaction between PIP2 and the TRPM8 S1-S4 domain. Computational PIP2 docking to a human TRPM8 comparative model was performed to help localize where PIRT may bind TRPM8. Taken together, our data suggest a mechanism where TRPM8, PIRT, and PIP2 form a regulatory complex and PIRT modulation of TRPM8 arises, at least in part, by regulating local concentrations of PIP2 accessible to TRPM8.

MP58-20 TRANSIENT RECEPTOR POTENTIAL V4 (TRPV4)-ION CHANNEL-ACTIVE DRUGS MODIFY NORMAL AND PATHOLOGICAL URETER IN VIVO PERISTALSIS IN RATS

2016 ◽  
Vol 195 (4S) ◽  
Author(s):  
Philipp Dr. Weinhold ◽  
Frank Strittmatter ◽  
Christian Stief ◽  
Christian Gratzke ◽  
Francesco Montorsi ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor
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