Supercooling Agent Icilin Blocks a Warmth-Sensing Ion Channel TRPV3

Abstract

Transient receptor potential vanilloid subtype 3 (TRPV3) is a thermosensitive ion channel expressed in a variety of neural cells and in keratinocytes. It is activated by warmth (33–39°C), and its responsiveness is dramatically increased at nociceptive temperatures greater than 40°C. Monoterpenoids and 2-APB are chemical activators of TRPV3 channels. We found that Icilin, a known cooling substance and putative ligand of TRPM8, reversibly inhibits TRPV3 activity at nanomolar concentrations in expression systems like Xenopus laeves oocytes, HEK-293 cells, and in cultured human keratinocytes. Our data show that icilin's antagonistic effects for the warm-sensitive TRPV3 ion channel occurs at very low concentrations. Therefore, the cooling effect evoked by icilin may at least in part be due to TRPV3 inhibition in addition to TRPM8 potentiation. Blockade of TRPV3 activity by icilin at such low concentrations might have important implications for overall cooling sensations detected by keratinocytes and free nerve endings in skin. We hypothesize that blockage of TRPV3 might be a signal for cool-sensing systems (like TRPM8) to beat up the basal activity resulting in increased cold perception when warmth sensors (like TRPV3) are shut off.

Drofenine: a 2‐APB analog with improved selectivity for human TRPV3

“…), the TRPM8 agonist icilin (Sherkheli et al. ), 2,2‐diphenyltetrahydrofuran (a 2‐APB analog) (Chung et al. ), and isopentenyl pyrophosphate (Bang et al.…”

The Ca2+-Permeable Cation Transient Receptor Potential TRPV3 Channel: An Emerging Pivotal Target for Itch and Skin Diseases

“…To date, there is a lack of specific TRPV3 antagonists, although there are several TRPV3 antagonists including the anti-inflammatory lipid mediator 17(R)-resolvin D1 (17R-RvD1) (Bang et al, 2012), the 2-APB structural analog diphenyltetrahydrofuran (Chung et al, 2005), the TRPM8 agonist icilin (Sherkheli et al, 2012), and isopentenyl pyrophosphate (Bang et al, 2011). However, these TRPV3 antagonists are not specific.…”

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

“…Icilin is a synthetic compound that behaves as an agonist of TRPM8 (about 200-fold more potent than menthol), 26,139 but also suppressed TRPM8 current activation by other agonists, 22 and modulates TRPV3, 140 and TRPA1. 22 Therefore, icilin has been and continues being used as a pharmacological tool for studying TRP channels.…”