Pharmacol Res. 2014 Sep;87:113-22. doi: 10.1016/j.phrs.2014.06.015. Epub 2014 Jul 8.
Functional and biochemical interaction between PPARalpha receptors and TRPV1 channels: Potential role in PPARalpha agonists-mediated analgesia.
Ambrosino, P., Soldovieri, M. V., De Maria, M., Russo, C., Taglialatela, M.,
["Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: paolo.ambrosino@unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: mariavirginia.soldovieri@unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: michela.demaria@studenti.unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: claudio.russo@unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy; Dept. of Neuroscience, Section of Pharmacology, University of Naples Federico II, Naples, Italy. Electronic address: m.taglialatela@unimol.it."]
["Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: paolo.ambrosino@unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: mariavirginia.soldovieri@unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: michela.demaria@studenti.unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: claudio.russo@unimol.it.", "Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy; Dept. of Neuroscience, Section of Pharmacology, University of Naples Federico II, Naples, Italy. Electronic address: m.taglialatela@unimol.it."]
Transient receptor potential vanilloid type-1 (TRPV1) channels expressed in primary afferent neurons play a critical role in nociception triggered by endogenous and exogenous compounds. In the present study, the functional and biochemical interaction between TRPV1 channels and type-alpha peroxisome proliferator-activated receptors (PPARalpha) has been investigated. In TRPV1-expressing CHO cells, patch-clamp studies revealed that acute application of the PPARalpha agonists clofibrate (CLO; 0.1-100 muM), WY14643 (1-300 muM), or GW7647 (0.1-100 nM) activated TRPV1 currents in a concentration-dependent manner, with EC50s of 5.3 +/- 0.8 muM, 13.0 +/- 1.2 muM, and 12.7 +/- 0.3 nM, respectively. The role of PPARalpha in these pharmacological responses was confirmed by the ability of the PPARalpha antagonist GW6471 (10 muM) to block CLO-, WY14643- and GW7647-induced TRPV1 activation, and by the observation that modulation of PPARalpha levels via siRNA-mediated suppression or PPARalpha over-expression affected TRPV1 channel activation by PPARalpha agonists accordingly. In cells cotransfected with PPARalpha and TRPV1, PPARalpha receptors were detected in TRPV1-immunoprecipitated fractions. When compared to capsaicin (CAP), TRPV1 currents activated by PPARalpha agonists showed a higher degree of acute desensitization and tachyphylaxis; moreover, GW7647, when pre-incubated at a concentration (1nM) unable to activate TRPV1 currents per se, desensitized CAP-induced TRPV1 currents. Finally, a sub-effective concentration of each PPARalpha agonist inhibited TRPV1-dependent bradykinin-induced [Ca(2+)]i transients in sensory neurons. Collectively, these results provide evidence for a PPARalpha-mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARalpha agonists in vivo.
PMID: 25014183
 Screening
Validation: In vitro validation
Validation: In vivo validation
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| Experimental screening | Non-experimental screening | Reference | ||||||||
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| TRP channel | Interactor | Method | Species | Region | Species | Organ/tissue | Sample type | |||
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PPARơ | Inference | Prediction | 25014183 | |||||
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Screening
Validation: In vitro validation
Validation: In vivo validation
Characterization
Functional consequence
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| Validation: In vivo validation
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| Cell or tissue | Cell or tissue | TRP channel construct | Interactor construct | |||||||
| TRP channel | Interactor | Method | Species | Region | Species | Region | ||||
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PPARơ | Co-immunoprecipitation | CHO | Rat | Full-length | Rat | Full-length | 25014183 | |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
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Screening
Validation: In vitro validation
Validation: In vivo validation
Characterization
Functional consequence
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| Functional consequence
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| TRP channel | Interactor | Method | Post-translational modification | Subcellular trafficking | Activity | Reference | ||||||
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PPARơ | Calcium measurement | Activation | 25014183 | |||||||
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PPARơ | Patch clamp | Activation | 25014183 | |||||||
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)