Dissecting TRPV1: Lessons to be learned?

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

“…Cyclic nucleotide binding and voltage changes work synergistically to control opening and closing of HCN channels, just as Ca 2+ and voltage work together to control K Ca channels. Members of the TRP family of channels are regulated by diverse physiologic stimuli, including lipid second messengers such as phosphatidylinositol phosphates, heat, cold, and noxious chemicals (Bautista et al, 2007;Wu et al, 2010a;Grimm et al, 2011). Recent high-resolution structures show that the temperature-sensitive TRPV channels have a transmembrane core with a fold like K V or Na V channels plus a large intracellular TRP domain that interacts with the transmembrane core of the channel through the S4-S5 linker and is well positioned for allosteric interactions with the voltage-sensing domains .…”

3D Structures and Molecular Evolution of Ion Channels

“…An interesting example is TRPV channels, which share with voltagesensing P-loop channels folding of the pore domain and four "voltage-sensing" domains with apparently very similar structural organization. However, TRPV channels are not sensitive to voltage and can be activated by various stimuli, including temperature, pH, and ligands that bind to distinct sites [20]. Unexpectedly, these specific features appeared in evolution without incorporation of specific domains.…”

Investigation of the transient receptor potential vanilloid 1 (TRPV1) ion channel

“…Nociceptive thresholds reported in neonatal CAPS-treated animals are apparently contradictory. Several groups have reported a small increase in the thermal nociceptive threshold [171,192] whereas others detected little if any effect in hot plate tests [193,194]. It has been claimed that perineural RTX selectively inhibits inflammatory hyperalgesia [195].…”

“…Wang et al reported that the first four TMs (TM1-4) of TRPV1 dictate whether the activity of a fully CAPSbound receptor can be further enhanced by protons, and a glutamate residue (E536) in the linker between TM3 and TM4 of hTRPV1 is critical in the modulation by protons and in the further stimulation of fully liganded TRPV1 [75,194].…”

“…[ 177,194,195,198,199] Y666 A Its mutation resulted in non-functional channel. [175] I668 A Its mutation reduced CAPS sensitivity, heat-induced current responses and heatpotentiated CAPS currents.…”