N-terminal tetrapeptide T/SPLH motifs contribute to multimodal activation of human TRPA1 channel

0461578 - FGÚ 2017 RIV GB eng J - Článek v odborném periodiku
Hynková, Anna - Maršáková, Lenka - Vašková, Jana - Vlachová, Viktorie
N-terminal tetrapeptide T/SPLH motifs contribute to multimodal activation of human TRPA1 channel.
Scientific Reports. Roč. 6, Jun 27 (2016), s. 28700. ISSN 2045-2322. E-ISSN 2045-2322
Grant CEP: GA ČR(CZ) GA15-15839S
Institucionální podpora: RVO:67985823
Klíčová slova: ankyrin receptor subtype 1 * transient receptor potential * gating * ankyrin repeat * whole-cell electrophysiology * N-terminus * mutagenesis
Kód oboru RIV: FH - Neurologie, neurochirurgie, neurovědy
Impakt faktor: 4.259, rok: 2016

Human transient receptor potential ankyrin channel 1 (TRPA1) is a polymodal sensor implicated in pain, inflammation and itching. An important locus for TRPA1 regulation is the cytoplasmic N-terminal domain, through which various exogenous electrophilic compounds such as allyl-isothiocyanate from mustard oil or cinnamaldehyde from cinnamon activate primary afferent nociceptors. This major region is comprised of a tandem set of 17 ankyrin repeats (AR1-AR17), five of them contain a strictly conserved T/SPLH tetrapeptide motif, a hallmark of an important and evolutionarily conserved contribution to conformational stability. Here, we characterize the functional consequences of putatively stabilizing and destabilizing mutations in these important structural units and identify AR2, AR6, and AR11-13 to be distinctly involved in the allosteric activation of TRPA1 by chemical irritants, cytoplasmic calcium, and membrane voltage. Considering the potential involvement of the T/SP motifs as putative phosphorylation sites, we also show that proline-directed Ser/Thr kinase CDK5 modulates the activity of TRPA1, and that T673 outside the AR-domain is its only possible target. Our data suggest that the most strictly conserved N-terminal ARs define the energetics of the TRPA1 channel gate and contribute to chemical-, calcium- and voltage-dependence.
Trvalý link: http://hdl.handle.net/11104/0261244