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.
Highlights
In recent years, a part of the scientific community has invested considerable efforts and attention in the structural and physio(patho)logical characterization of the transient receptor potential protein melastatin family (TRPM), a member of the TRP superfamily [1,2,3]
Sensory neurons expressing TRPV1, TRPA1 and transient receptor potential melastatin subtype 8 (TRPM8) have been found in the mouse and monkey cornea, constituting accessible tissue sources to further explore the molecular mechanisms of pathological eye hyperalgesia states
A recent article demonstrated that TRPM8 channels are expressed in different populations of terminal corneal C-fibers, separated from those that express TRPV1 and TRPA1, which are co-localized in axons [109]
Summary
A part of the scientific community has invested considerable efforts and attention in the structural and physio(patho)logical characterization of the transient receptor potential protein melastatin family (TRPM), a member of the TRP superfamily [1,2,3]. Functional TRPM8 alterations have been observed in various inflammatory and neuropathic pain states, including dry eye disease (DED) [61,62,63] and migraine [64], oxaliplatin-based cancer peripheral neuropathy [65,66], spinal cord injury [67,68], or after sustained morphine administration [69] These states are characterized by cold hypersensitivity, which appear as a common symptom, induced by either TRPM8 overexpression or genetic TRPM8 variants [62,66,68,70]. The review covers newly described agonist and antagonist modulators, their contribution to the pharmacological characterization of the channel, as well as their evolution to clinical trials
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