Structure of Thermally Activated TRP Channels

Abstract

Temperature sensation is important for adaptation and survival of organisms. While temperature has the potential to affect all biological macromolecules, organisms have evolved specific thermosensitive molecular detectors that are able to transduce temperature changes into physiologically relevant signals. Among these thermosensors are ion channels from the transient receptor potential (TRP) family. Prime candidates include TRPV1–4, TRPA1, and TRPM8 (the so-called “thermoTRP” channels), which are expressed in sensory neurons and gated at specific temperatures. Electrophysiological and thermodynamic approaches have been employed to determine the nature by which thermoTRPs detect temperature and couple temperature changes to channel gating. To further understand how thermoTRPs sense temperature, high-resolution structures of full-length thermoTRPs channels will be required. Here, we will discuss current progress in unraveling the structures of thermoTRP channels.

Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach

“…We used a homology model generated by fragments of the resolved structure of the Kv1.2 Shaker channel as the overall template 50 . To date, the only additional structure available is the recently resolved TRPV1 structure 51 ; however, TRPV1 does not have a significantly high degree of similarity with TRPM8 with respect to our model (pairwise alignment BLOSUM62 score 0.39 vs 0.35) 52 . Moreover, TRPV1 structure allows for reliable generation of only the transmembrane bundle.…”

“…To date, approximately 120 different chemotypes can be enumerated among all known TRPM8 antagonists 47 . These chemotypes include the following examples: benzyloxybenzene derivatives, such as AMTB (Bayer) 68 , Cpd 87 (Glenmark, WO2010010435) and Cpd 14 (Pfizer) 69 ; arylamides, arylsulfonamides and close analogs, such as RQ-00203078 705047 (RaQualia) 51 and Cpd 7 s (Janssen) 70 ; AMGEN tetrahydroisoquinolines derivatives 71 ; chromanes and chromenes, such as Cpd 8f (Glenmark) 24 and Cannabichromene (GW Pharmaceuticals) 72 , respectively; azetidin-2-ones 23 ; and diphenylpyrazoles (Kissei, WO2016208602) Napththyl derivatives have the proper chemical characteristics and tractability to overcome the lead optimization process. The compound 1 lead presented in this paper demonstrated to be potent and selective before any chemical optimization.…”

CPEB3 Deficiency Elevates TRPV1 Expression in Dorsal Root Ganglia Neurons to Potentiate Thermosensation

“…We wondered about the molecular changes in CPEB3-depleted DRG neurons that could lead to elevated thermal response to noxious heat ( Fig 2B ). There are at least six temperature sensors expressed in sensory neurons and gated at specific temperatures, including TRPV1 (> 43°C), TRPV2 (> 52 o C), TRPV3 (> 30–39 o C), TRPV4 (> 25–35°C), TRPM8 (< 20–28 o C) and TRPA1 (< 17 o C) [ 29 – 35 ]. Compared with TRPV3 and TRPV4, TRPV1 and TRPV2 are more abundantly expressed in DRG and respond to noxious heat [ 35 , 36 ].…”

“…There are at least six temperature sensors expressed in sensory neurons and gated at specific temperatures, including TRPV1 (> 43°C), TRPV2 (> 52 o C), TRPV3 (> 30–39 o C), TRPV4 (> 25–35°C), TRPM8 (< 20–28 o C) and TRPA1 (< 17 o C) [ 29 – 35 ]. Compared with TRPV3 and TRPV4, TRPV1 and TRPV2 are more abundantly expressed in DRG and respond to noxious heat [ 35 , 36 ]. Thus, we first used RNA-immunoprecipitation to examine the association between CPEB3 and transcripts encoding heat-sensing channels, TRPV1 and TRPV2, and a cold-sensing channel, TRPA1.…”

The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease

“…In this model, association with additional proteins would be required to impart TRPM1 with the salient features characteristic of ON-BC transduction channels. In agreement with this idea, structural studies with a purified TRPM1 protein indicate that it forms a dimer without a classical ionic pore (Agosto et al 2014), which for TRP channels typically requires tetrameric organization of protomers (Cohen & Moiseenkova-Bell 2014). Since many TRP family members frequently associate with one another, one straightforward possibility could be that TRPM1 forms heteromeric complexes with another TRP channel to build transduction channels.…”