Abstract
For a long time, the focus of trigeminal chemoperception has rested almost exclusively on TRP channels. However, two-pore domain (K2P) potassium channels have recently been identified as targets for substances associated with typical trigeminal sensations, such as numbing and tingling. In addition, they have been shown to be modulated by several TRP agonists. We investigated whether the pungent substances piperine, capsaicin, 6-gingerol and polygodial have an effect on human K2P channels. For this purpose, we evaluated the effects of these pungent substances on both wild-type and mutant K2P channels by means of two-electrode voltage-clamp experiments using Xenopus laevis oocytes. All four pungent substances were found to inhibit the basal activity of TASK-1 (K2P 3.1), TASK-3 (K2P 9.1), and TRESK (K2P 18.1) channels. This inhibitory effect was dose-dependent and, with the exception of polygodial on TASK-1, fully reversible. However, only piperine exhibited an IC50 similar to its reported EC50 on TRP channels. Finally, we observed for TASK-3 that mutating H98 to E markedly decreased the inhibition induced by piperine, capsaicin, and 6-gingerol, but not by polygodial. Our data contribute to the relatively sparse knowledge concerning the pharmacology of K2P channels and also raise the question of whether K2P channels could be involved in the pungency perception of piperine.
Highlights
In modern cuisine, numerous spices, such as black peppercorns (Piper nigrum), chili pepper (Capsicum annuum), mountain pepper (Tasmannia lanceolata) or ginger (Zingiber officinalis), have been appreciated worldwide for their ability to add a pungent orosensory impression to dishes
We investigated whether the pungent substances piperine, capsaicin, 6-gingerol and polygodial have an effect on human K2P channels
PUNGENT COMPOUNDS INHIBIT TASK-1, TASK-3 AND TRESK IN A DOSE-DEPENDENT MANNER Piperine To investigate whether piperine has an effect on human K2P channels, we used Xenopus laevis oocytes as expression system for human TREK-1, TASK-1, TRAAK, TASK-3, TREK-2, and TRESK
Summary
Numerous spices, such as black peppercorns (Piper nigrum), chili pepper (Capsicum annuum), mountain pepper (Tasmannia lanceolata) or ginger (Zingiber officinalis), have been appreciated worldwide for their ability to add a pungent orosensory impression to dishes. After several genetic and functional studies, the pungency of these spices is believed to be based mainly on the activation of two members of the transient receptor potential (TRP) family, TRPV1 and TRPA1. These two polymodic, non-selective cation channels, which play a role in pain perception, are expressed on free afferent nerve endings of trigeminal neurons in the oral cavity (Calixto et al, 2005). Other pungent Piper nigrum amides such as, e.g., piperolein B, were reported to activate the ion channels TRPA1 and TRPV1 (Correa et al, 2010; Okumura et al, 2010). Polygodial, the pungent drimane-type sesquiterpene dialdehyde from mountain pepper (Barnes and Loder, 1962), and vanilloids such as, e.g., 6-gingerol from ginger rhizomes (Belitz et al, 2004), have been identified as TRPA1 and TRPV1 activators (Dedov et al, 2002; Witte et al, 2002; Bandell et al, 2004; Calixto et al, 2005; André et al, 2006; Escalera et al, 2008; Iwasaki et al, 2009; Morera et al, 2012)
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