TRP Channels: Their Function and Potentiality as Drug Targets

Abstract

The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors as well as signal integrators. Several members of the TRP family are sensitive to changes in cellular redox status. Among them, TRPA1 is remarkably susceptible to various oxidants and is known to mediate neuropathic pain and respiratory, vascular, and gastrointestinal functions, making TRPA1 an attractive therapeutic target. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. Most recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol) and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. On the other hand, TRPCs are typical receptor-activated Ca2+-permeable cation channels, which sense messenger molecules generated downstream of phospholipase activation. Previously, activation of TRPC3 and TRPC6 by diacylglycerol has been reported to play important roles in the pathogenesis of cardiac hypertrophy. Also, a pyrazole compound, Pyr3, which selectively inhibits TRPC3, suppresses cardiac hypertrophy in animal models in vitro and in vivo. We have most recently found that Pyr3 and related compounds are effective in suppressing cardiac fibrosis and ischemia responsible for cardiac remodeling as well. Thus, in this chapter, we describe the molecular pharmacology of TRP modulators and discuss their modulatory mechanisms and pharmacological actions.