High-Throughput Approaches to Studying Mechanisms of TRP Channel Activation

Excerpt

Transient receptor potential (TRP) channels are calcium-permeable nonselective cation channels with six transmembrane (TM) domains and a putative pore loop between TM5 and TM6. About 28 mammalian TRP channels have been identified so far, with different numbers of splicing variants for each channel gene. TRP channels have been classified into six different subgroups, including TRPV (1–6), TRPM (1–8), TRPC (1–7), TRPA1, TRPP (1–3), and TRPML (1–3), according to their sequence similarities. In general, TRP channels are involved in calcium handling (e.g., intracellular calcium mobilization and calcium reabsorption) and a broad range of sensory modalities, including pain, temperature, taste, etc.^, TRP channelopathies are part of important mechanisms in a variety of diseases such as neurodegenerative disorders, diabetes mellitus, inflammatory bowel diseases, epilepsy, cancer, etc.^– Several members of the TRP family, TRPV1-4, TRPM8, and TRPA1, also called “ThermoTRPs,” are involved in the detection of temperature changes, thus acting as the molecular thermometers of our body.^– In addition, they are also polymodal nociceptors that integrate painful stimuli such as noxious temperatures and chemical insults. For example, TRPV1 channel mediates thermal hyperalgesia and pain induced by capsaicin and acid.^,– TRPA1 is a nociceptor that integrates many noxious environmental stimuli including oxidants and electrophilic agents.^,, Recently, gene deletion animals have been created to study the role of TRP channels in pain and nociception, and involvement of TRPV1, TRPV3, TRPV4, and TRPA1 in nociception has been confirmed.^– The physiology and pathophysiology of TRP channels have been covered in some excellent recent reviews^–,– and will not be discussed in this chapter.