TRPA1 modulation by its lipid environment and physiological functions in skin-derived cells
Final Report Abstract
The funded project initially aimed at investigating whether a modulation of the lipid environment or the application of membrane curvature influences TRPA1-gating with regard to a possible mechano-activation. The co-expression of an 1-BAR-containing protein together with TRPA1 resulted in a reduced activity of the channel. However, this was not specific for TRPA1 but also applied to other TRP channels. A demonstration of robust mechanical gating could also not be achieved with other methods applied. We then focused the project on examining a possible physiological role of TRPA1 within the gastrointestinal tract. We could show that drugs, which elicit significant gastrointestinal side effects, such as apomorphine and the thienopyridine antiplatelet drugs ticlopidine and Clopidogrel, cause a release of serotonin from enterochromaffin-like cells. This is conferred via a TRPA1-dependent increase in [Ca2+]i, making TRPA1 a possible candidate for the transmission of adverse side effects within the gastrointestinal tract during pharmacotherapy. We also included a second member of the TRP channel family, TRPC5, in our studies. For TRPC5, two drugs could be identified, which can directly activate and inhibit TRPC5 activity. The drugs were effective both in a heterologous expression system but also in the U87 astrocytoma-glioblastoma cell, endogenously expressing TRPC5.
Publications
- (2012). TRPA1 is functionally expressed in melanoma cells but is not critical for impaired proliferation caused by allyl isothiocyanate or cinnamaldehyde. Naunyn Schmiedebergs Arch Pharmacol, 385, 555-563
Oehler, B, Scholze, A, Schaefer, M & Hill, K
(See online at https://doi.org/10.1007/s00210-012-0747-x) - (2013). Apomorphine is a bimodal modulator of TRPA1 channels. Mol Pharmacol, 83, 542-551
Schulze, A, Oehler, B, Urban, N, Schaefer, M & Hill, K
(See online at https://doi.org/10.1124/mol.112.081976) - (2014). Riluzole activates TRPC5 channels independently of PLC activity. Br J Pharmacol, 171, 158-170
Richter, JM, Schaefer, M & Hill, K
(See online at https://doi.org/10.1111/bph.12436) - (2014). Transient receptor potential ankyrin 1 (TRPA1) channel activation by the thienopyridine-type drugs ticlopidine, clopidogrel, and prasugrel. Cell Calcium, 55, 200-207
Schulze, A, Hartung, P, Schaefer, M & Hill, K
(See online at https://dx.doi.org/10.1016/j.ceca.2014.02.014)
