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 signifi cant 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 Ca 2+ -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 fi brosis 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.

LLLT enhance cyclophosphamide induced TRPM2 channel activation in human colon cancer cells

“…TRP channels respond well to oxidative stress mediators such as: reactive oxygen species (ROS), reactive nitrogen species (RNS) and other electrophiles. The transient receptor potential melastatin-2 (TRPM2) channel, which is the fi rst identifi ed ROS sensitive channel, is activated by hydrogen peroxide (H 2 O2) and is the mediator of numerous cellular responses including cell death and chemokine production (4). It has been reported that TRPM2 channels have crucial effects on migration and cell death in tumour cells and immune system cells and its expression is enhanced significantly in adenocarcinomas such as: breast cancer, head and neck, bladder, liver, pancreas, colon and lung adenocarcinomas (5,6).…”

Synergic and comparative effect of 5-fluorouracil and leucoverin on breast and colon cancer cells through TRPM2 channels

“…Transient receptor potential (TRP) protein was fi rst identifi ed in Drosophila trp genes in 1989 (5). The TRP protein family contains different groups of calcium ion (Ca 2+ ) permeable and non-selective cation channels and is found in many living organisms (6,7,8).…”

“…There are 6 subtypes of TRP channels; TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystic kidney disease), TRPML (mucolipin) and TRPA (ankyrin) TRP channels contain tetrameric subunit stoichiometry and each subunit contains cytoplasmic N and C-terminal regions, 6 transmembrane (TM) domains, and TM5-TM6 interspaces (9). TRP channels are responsive to stimuli such as receptor stimulation, heat, plantderived compounds, environmental irritants, mechanical stress, pH, intra-and extracellular voltage, and respond physiologically and pathologically (5,6,(7)(8)(9)(10). In addition, TRP channels respond fairly well to oxidative stress mediators such as: reactive oxygen species (ROS), reactive nitrogen species (RNS), and other electrophiles (11)(12)(13)(14).…”

“…Intracellular Ca 2+ is involved in the activation of TRP channels through receptor stimulation and enzymes such as the Ca 2+ dependent protein phosphatase, therefore it plays an important role in oxidative stress and apoptosis (5,18). It is known that chemotherapeutic agents increase intracellular Ca 2+ levels by free oxygen radi-cals in the cell and lead to oxidative stress.…”

Calcium Chloride (CaCl2) : Characteristics and Molecular Interaction in Solution

“…Karakteristik (232) dari Kalsium Klorida merupakan memiliki 3 struktur (73) kristal yaitu ortorombik, tetragonal, dan trigonal. Kalsium klorida boleh berfungsi sebagai sumber ion (74)(75)(76)(77)(78) kalsium dalam larutan aqua kerena sifat kalsium klorida yang boleh larut dalam air. Sifat (79) ini berguna untuk mengeluarkan ion daripada larutan (80) .…”