Characterisation of TRPM8 as a pharmacophore receptor

Inhibition of TRPM8 by Icilin Distinct from Desensitization Induced by Menthol and Menthol Derivatives

“…Icilin induced a large but transient inward current, whereas WS-12 evoked only a small effect. This would be in line with the previous conclusion that icilin and WS-12 used common mechanisms possibly mediated by common binding sites (24). However, this view was challenged when the experiments were repeated in the absence of Ca 2ϩ or, more specifically, under conditions where the extracellular and intracellular Ca 2ϩ concentrations were strongly buffered to below 10 nM (Fig.…”

“…Thus, a distinct channel region that specifically controls menthol sensitivity has not yet been identified. Recently, some carboxyamide derivatives were characterized as potent TRPM8 agonists and proposed as potential candidates for the development of anti-cancer drugs (23,24). Although the chemical structures of the carboxyamides more closely resemble that of menthol than of icilin, it has been suggested that at least one of these compounds, WS-12, acts like icilin on TRPM8 (23).…”

“…For instance, only the activation of TRPM8 by icilin depends on the presence of intracellular Ca 2ϩ (3,18) and is modulated by intracellular pH in the physiological range (22). Furthermore, although both icilin and menthol induce only transient currents, the current decline is much slower when menthol is the stimulus (18,23,24). It has been proposed that the decline after menthol stimulation represents desensitization involving depletion of phosphatidylinositol 4,5-bisphosphate; the desensitization in turn depends on intracellular Ca 2ϩ or on Ca 2ϩ influx through the open channel (13).…”

Molecular mechanisms underlying Ca2+-mediated motility of human pancreatic duct cells

“…TRPC and NCX have been described in mammalian tissues for decades, but very little is known about the expression and function of these proteins in human pancreatic cancer cells (4,22,32). Although the role of TRP channels has been reported in colorectal, colon, thyroid, breast, ovarian, and prostate cancer (7,64), the involvement of TRP channels and NCX in pancreatic cancer development is currently unexplored. Pancreatic cancer is the fourth leading cause of cancerrelated death in the United States, and nearly all patients diagnosed with pancreatic cancer die from a cancer-related death (24,26,52), with a 3% 5-year survival rate following diagnosis (43).…”

Ion Channels as Promising Therapeutic Targets for Melanoma

“…demonstrated that TRPM8 activation by agonists suppresses human melanoma cell viability (Yamamura et al, 2008a). Interestingly, numerous classical TRPM8 agonists are known, in addition to novel agonists (Bodding et al, 2007) that may be useful to treating most cancers in which TRPM8 channel is overexpressed in comparison to the corresponding normal tissue. Because of their inocuity, they represent a formidable pharmacological tool to evaluate this channel as target to melanoma therapy.…”