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Title

Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity

AuthorsGomis, Ana; Quirce, Susana; Viana, Félix; Belmonte, Carlos; Planells-Cases, Rosa
KeywordsPain
Ionotropic receptors
Pepducin
Analgesia
Inflammation
Issue DateMay-2011
PublisherFederation of American Societies for Experimental Biology
CitationFASEB Journal - Federation of American Societies for Experimental Biology 25(5): 1628-1640 (2011)
AbstractThe transient receptor potential vanilloid 1 (TRPV1) channel is a thermosensory receptor implicated in diverse physiological and pathological processes. The TRP domain, a highly conserved region in the C terminus adjacent to the internal channel gate, is critical for subunit tetramerization and channel gating. Here, we show that cell-penetrating, membrane-anchored peptides patterned after this protein domain are moderate and selective TRPV1 antagonists both in vitro and in vivo, blocking receptor activity in intact rat primary sensory neurons and their peripheral axons with mean decline time of 30 min. The most potent lipopeptide, TRP-p5, blocked all modes of TRPV1 gating with micromolar efficacy (IC 50<10 μM), without significantly affecting other thermoTRP channels. In contrast, its retrosequence or the corresponding sequences of other TRPV channels did not alter TRPV1 channel activity (IC 50>100 μM). TRP-p5 did not affect the capsaicin sensitivity of the vanilloid receptor. Our data suggest that TRP-p5 interferes with protein-protein interactions at the level of the TRP domain that are essential for the "conformational" change that leads to gate opening. Therefore, these palmitoylated peptides, which we termed TRPducins, are noncompetitive, voltage-independent, sequence-specific TRPV1 blockers. Our findings indicate that TRPducin-like peptides may embody a novel molecular strategy that can be exploited to generate a selective pharmacological arsenal for the TRP superfamily of ion channels.
DescriptionAna Gomis, [et al.]. 13 p., 7 figures, 1 table and references
Publisher version (URL)http://dx.doi.org/10.1096/fj.10-174433
URIhttp://hdl.handle.net/10261/54937
DOI10.1096/fj.10-174433
ISSN0892-6638
E-ISSN1530-6860
Appears in Collections:(IN) Artículos
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