TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Abstract

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

“…TRPM8 is involved in the abnormal bladder sensation, and its potential as an attractive molecular target in the lower urinary tract has been assessed 4–7 . Recently, several TRPM8 antagonists have been reported, and inhibition of TRPM8 would be a promising therapeutic option for hypersensitive bladder disorders 8–13 …”

Transient Receptor Potential (TRP) and Thermoregulation in Animals: Structural Biology and Neurophysiological Aspects

“…Its cytoplasmatic region comprises the C-terminal and D-terminal domains. The latter includes four melastatin zones [ 78 ]. The TRPA1 channel is another cold sensor.…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…In addition, the expression of the same mSR in different but strictly connected tissues in the TME also offers the possibility to intervene not only on the tumorigenic process itself but also in cancer-sustaining mechanisms. Synthetic and natural compounds able to bind mSRs here presented-apart from TRPM8 and GPER, whose molecular modulators were recently and excellently reviewed [203,204]-are listed in Table 1. PaCa-2 cells (pancreatic cancer) RACK1, alpha-Actinin-1 Reduced PGRMC1 interactions with the actin cytoskeleton [225] Human granulosa/luteal cell B-cell lymphoma 2 (BCL2) pathway Increased PGRMC1 monomeric form, increased proapoptotic Harakiri (Hrk) expression [226] Due to the relative novelty of mSRs as mediators of steroid signaling, studies on mSRactive compounds here presented were limited to the pre-clinical phase.…”

“…In addition, the expression of the same mSR in different but strictly connected tissues in the TME also offers the possibility to intervene not only on the tumorigenic process itself but also in cancer-sustaining mechanisms. Synthetic and natural compounds able to bind mSRs here presented—apart from TRPM8 and GPER, whose molecular modulators were recently and excellently reviewed [ 203 , 204 ]—are listed in Table 1 .…”