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

作者：Valente Pierluigi; Fernandez Carvajal Asia; Camprubi Robles Maria; Gomis Ana; Quirce Susana; Viana Felix; Fernandez Ballester Gregorio; Gonzalez Ros Jose M; Belmonte Carlos; Planells Cases Rosa; Ferrer Montiel Antonio^*

来源：The FASEB Journal, 2011, 25(5): 1628-1640.

DOI：10.1096/fj.10-174433

• pain
• ionotropic receptors
• pepducin
• analgesia
• inflammation

The 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 mu M), 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 mu M). 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.-Valente, P., Fernandez-Carvajal, A., Camprubi-Robles, M., Gomis, A., Quirce, S., Viana, F., Fernandez-Ballester, G., Gonzalez-Ros, J. M., Belmonte, C., Planells-Cases, R., Ferrer-Montiel, A. Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity. FASEB J. 25, 1628-1640 (2011). www.fasebj.org

• 出版日期2011-5