J Biol Chem. 2012 Oct 26;287(44):37552-63. doi: 10.1074/jbc.M112.391847. Epub 2012 Sep 5.
beta-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel.
Por, E. D., Bierbower, S. M., Berg, K. A., Gomez, R., Akopian, A. N., Wetsel, W. C., Jeske, N. A.,
["Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, USA."]
["Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229, USA."]
Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel activated by multiple stimuli and is implicated in a variety of pain disorders. Dynamic sensitization of TRPV1 activity by A-kinase anchoring protein 150 demonstrates a critical role for scaffolding proteins in nociception, yet few studies have investigated scaffolding proteins capable of mediating receptor desensitization. In this study, we identify beta-arrestin-2 as a scaffolding protein that regulates TRPV1 receptor activity. We report beta-arrestin-2 association with TRPV1 in multiple cell models. Moreover, siRNA-mediated knockdown of beta-arrestin-2 in primary cultures resulted in a significant increase in both initial and repeated responses to capsaicin. Electrophysiological analysis further revealed significant deficits in TRPV1 desensitization in primary cultures from beta-arrestin-2 knock-out mice compared with wild type. In addition, we found that beta-arrestin-2 scaffolding of phosphodiesterase PDE4D5 to the plasma membrane was required for TRPV1 desensitization. Importantly, inhibition of PDE4D5 activity reversed beta-arrestin-2 desensitization of TRPV1. Together, these results identify a new endogenous scaffolding mechanism that regulates TRPV1 ligand binding and activation.
PMID: 22952227
 Screening
Validation: In vitro validation
Validation: In vivo validation
Characterization
Functional consequence
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Screening
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| Experimental screening | Non-experimental screening | Reference | ||||||||
| TRP channel construct | Interactor source | |||||||||
| TRP channel | Interactor | Method | Species | Region | Species | Organ/tissue | Sample type | |||
| TRPV1 |
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Ƣ-arrestin 2 | Speculation | Prediction | 22952227 | |||||
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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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| Validation: In vivo validation
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| Assay with endogenous proteins | Assay with overexpressed proteins | Reference | ||||||||
| Cell or tissue | Cell or tissue | TRP channel construct | Interactor construct | |||||||
| TRP channel | Interactor | Method | Species | Region | Species | Region | ||||
| TRPV1 |
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Ƣ-arrestin 2 | Co-immunoprecipitation | Rat trigeminal ganglia sensory neuron | 22952227 | |||||
(:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
|
Screening
Validation: In vitro validation
Validation: In vivo validation
Characterization
Functional consequence
|
top
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| Functional consequence
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| TRP channel | Interactor | Method | Post-translational modification | Subcellular trafficking | Activity | Reference | ||||||
| TRPV1 |
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Ƣ-arrestin 2 | Calcium measurement | Desensitization | 22952227 | |||||||
| TRPV1 |
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Ƣ-arrestin 2 | In vivo PTM assay | Dephosphorylation | 22952227 | |||||||
(:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)