| First Author | Lin King JV | Year | 2019 |
| Journal | Cell | Volume | 178 |
| Issue | 6 | Pages | 1362-1374.e16 |
| PubMed ID | 31447178 | Mgi Jnum | J:298782 |
| Mgi Id | MGI:6488697 | Doi | 10.1016/j.cell.2019.07.014 |
| Citation | Lin King JV, et al. (2019) A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain. Cell 178(6):1362-1374.e16 |
| abstractText | TRPA1 is a chemosensory ion channel that functions as a sentinel for structurally diverse electrophilic irritants. Channel activation occurs through an unusual mechanism involving covalent modification of cysteine residues clustered within an amino-terminal cytoplasmic domain. Here, we describe a peptidergic scorpion toxin (WaTx) that activates TRPA1 by penetrating the plasma membrane to access the same intracellular site modified by reactive electrophiles. WaTx stabilizes TRPA1 in a biophysically distinct active state characterized by prolonged channel openings and low Ca(2+) permeability. Consequently, WaTx elicits acute pain and pain hypersensitivity but fails to trigger efferent release of neuropeptides and neurogenic inflammation typically produced by noxious electrophiles. These findings provide a striking example of convergent evolution whereby chemically disparate animal- and plant-derived irritants target the same key allosteric regulatory site to differentially modulate channel activity. WaTx is a unique pharmacological probe for dissecting TRPA1 function and its contribution to acute and persistent pain. |
