COX-2-selective inhibitors celecoxib and deracoxib modulate transient receptor potential vanilloid 3 channels.

BACKGROUND AND PURPOSE: The transient receptor potential vanilloid 3 (TRPV3) channel is a heat-sensitive ion channel, which is predominantly expressed in keratinocytes. TRPV3 channels are involved in numerous physiological and pathophysiological processes within the skin, including cutaneous nociception, temperature sensation and development of itch. The role of TRPV3 channels in such processes is poorly understood; therefore, the establishment of selective modulators of TRPV3 channels is highly desirable.

EXPERIMENTAL APPROACH: Novel TRPV3-modulating compounds were identified using fluorometric intracellular Ca2+ assays and further evaluated with electrophysiological techniques.

KEY RESULTS: TRPV3 activity, elicited by 2-aminoethoxydiphenyl borate (2-APB), was efficaciously enhanced by deracoxib and celecoxib, two COX-2-selective inhibitors. They exerted their potentiating effect via a direct interaction with TRPV3 as evident from excised inside-out recordings. Structurally-related COX-2 inhibitors affected TRPV3 channel gating to a much lesser degree. Similar results were obtained in HEK293 cells stably expressing cyan fluorescent protein-tagged mouse TRPV3 channels and in a mouse keratinocyte cell line, endogenously expressing TRPV3. The effects of celecoxib and deracoxib on TRPV3 were dependent on the stimulus used to activate TRPV3. While 2-APB and heat-activated TRPV3 channels were potentiated by celecoxib, carvacrol-activated channels were inhibited by celecoxib.

CONCLUSIONS AND IMPLICATIONS: We identified a new class of drugs that modulate TRPV3 channels. The most potent compound celecoxib is an approved analgesic and anti-inflammatory drug, which is currently being investigated for its topical application in the treatment of skin cancer. As TRPV3 is highly expressed in skin, celecoxib might affect TRPV3 activity in vivo when used at high local concentrations.