FASEB J. 2010 Jun;24(6):1958-70. doi: 10.1096/fj.09-151472. Epub 2010 Feb 23.
GABAA receptor associated protein (GABARAP) modulates TRPV1 expression and channel function and desensitization.
Lainez, S., Valente, P., Ontoria-Oviedo, I., Estevez-Herrera, J., Camprubi-Robles, M., Ferrer-Montiel, A., Planells-Cases, R.,
["Centro de Investigacion Principe Felipe, Valencia, Spain."]
["Centro de Investigacion Principe Felipe, Valencia, Spain."]
Transient receptor potential vanilloid (TRPV1) transduces noxious chemical and physical stimuli in high-threshold nociceptors. The pivotal role of TRPV1 in the physiopathology of pain transduction has thrust the identification and characterization of interacting partners that modulate its cellular function. Here, we report that TRPV1 associates with gamma-amino butyric acid A-type (GABA(A)) receptor associated protein (GABARAP) in HEK293 cells and in neurons from dorsal root ganglia coexpressing both proteins. At variance with controls, GABARAP augmented TRPV1 expression in cotransfected cells and stimulated surface receptor clustering. Functionally, GABARAP expression attenuated voltage and capsaicin sensitivity of TRPV1 in the presence of extracellular calcium. Furthermore, the presence of the anchor protein GABARAP notably lengthened the kinetics of vanilloid-induced tachyphylaxia. Notably, the presence of GABARAP selectively increased the interaction of tubulin with the C-terminal domain of TRPV1. Disruption of tubulin cytoskeleton with nocodazole reduced capsaicin-evoked currents in cells expressing TRPV1 and GABARAP, without affecting the kinetics of vanilloid-induced desensitization. Taken together, these findings indicate that GABARAP is an important component of the TRPV1 signaling complex that contributes to increase the channel expression, to traffic and cluster it on the plasma membrane, and to modulate its functional activity at the level of channel gating and desensitization.
PMID: 20179142

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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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GABARAP | Yeast two-hybrid | Rat | 1-414 | Rat | Brain | cDNA library | 20179142 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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Validation: In vitro validation
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Assay with recombinant proteins | Reference | |||||||||
TRP channel construct | Interactor construct | |||||||||
TRP channel | Interactor | Method | Species | Region | Expression system | Species | Region | Expression system | ||
TRPV1 |
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GABARAP | Fusion protein-pull down assay | Not used | Rat brain lysates | Human | Full-length | E. coli | 20179142 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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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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GABARAP | Fluorescence resonance energy transfer | HEK293 | Rat | Full-length | Human | Full-length | 20179142 | |
TRPV1 |
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GABARAP | Co-immunofluorescence staining | Neonatal rat dorsal root ganglion | 20179142 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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Characterization
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Binding region mapping | Stoichiometry | Affinity (Kd) | Reference | |||||||
TRP channel | Interactor | |||||||||
TRP channel | Interactor | Method | Species | Region | Species | Region | ||||
TRPV1 |
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GABARAP | Fusion protein-pull down assay | Rat | 1-414 | Human | 1-36 | 20179142 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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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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GABARAP | Calcium measurement | Inhibition | 20179142 | |||||||
TRPV1 |
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GABARAP | Patch clamp | Inhibition | 20179142 | |||||||
TRPV1 |
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GABARAP | Cell surface biotinylation | Increase in plasma membrane level | 20179142 |
(
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
