Tonantzitlolone is a nanomolar potency activator of transient receptor potential canonical 1/4/5 channels

作者：Rubaiy Hussein N; Ludlow Melanie J; Siems Karsten; Norman Katherine; Foster Richard; Wolf Dietmar; Beutler John A; Beech David J^*

来源：British Journal of Pharmacology, 2018, 175(16): 3361-3368.

DOI：10.1111/bph.14379

BACKGROUND AND PURPOSE
The diterpene ester tonantzitlolone (TZL) is a natural product, which displays cytotoxicity towards certain types of cancer cell such as renal cell carcinoma cells. The effect is similar to that of (-)-englerin A, and so, although it is chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels of the 1, 4 and 5 type (TRPC1/4/5 channels).
EXPERIMENTAL APPROACH
The effects of TZL on renal cell carcinoma A498 cells natively expressing TRPC1 and TRPC4, modified HEK293 cells overexpressing TRPC4, TRPC5, TRPC4-TRPC1 or TRPC5-TRPC1 concatemer, TRPC3 or TRPM2, or CHO cells overexpressing TRPV4 were studied by determining changes in intracellular Ca2+, or whole-cell or excised membrane patch-clamp electrophysiology.
KEY RESULTS
TZL induced an elevation of intracellular Ca2+ in A498 cells, similar to that evoked by englerin A. TZL activated overexpressed channels with EC50 values of 123nM (TRPC4), 83nM (TRPC5), 140nM (TRPC4-TRPC1) and 61nM (TRPC5-TRPC1). These effects of TZL were reversible on wash-out and potently inhibited by the TRPC1/4/5 inhibitor Pico145. TZL activated TRPC5 channels when bath-applied to excised outside-out but not inside-out patches. TZL failed to activate endogenous store-operated Ca2+ entry or overexpressed TRPC3, TRPV4 or TRPM2 channels in HEK 293 cells.
CONCLUSIONS AND IMPLICATIONS
TZL is a novel potent agonist for TRPC1/4/5 channels, which should be useful for testing the functionality of this type of ion channel and understanding how TRPC1/4/5 agonists achieve selective cytotoxicity against certain types of cancer cell.

• 出版日期2018-8