TRPM8, originally cloned as a prostate-specific protein, is a non-selective cation channel best known as a cold-and menthol-activated channel involved in thermosensation [2]. It is the main molecular entity responsible for cold transduction in thermoreceptor neurons, activated by low temperatures (8-26 °C or >10, <28 °C), voltage, pressure, cooling compounds, and hyperosmolarity [3,6]. It participates in various biological processes like cell proliferation, migration, apoptosis, and also has implications in maintaining Ca2+ homeostasis [8].

Numerous genome-wide association studies have implicated TRPM8 in migraine. It is expressed on sensory afferents innervating the meninges, and in pre-clinical migraine studies, activation of meningeal TRPM8 by exogenous agonists can either cause or alleviate headache behaviors depending on noxious stimuli to other meningeal afferents, similar to how cold can trigger and menthol can alleviate headache in humans [1]. TRPM8 also contributes to cold allodynia after nerve injury or inflammation and is necessary for cooling/menthol-based analgesia [1]. In the digestive system, its expression is associated with various physiological and pathological processes in organs like the esophagus, stomach, and pancreas [4]. Also, it has been reported to be involved in the progress of multiple cancers including prostate, pancreatic, and breast cancers [5]. In the lower urinary tract, it may contribute to the pathophysiology of bladder hypersensitivity, with its antagonist being a potential therapeutic target for bladder hypersensitive disorders [7].

In conclusion, TRPM8 plays essential roles in thermosensation, pain detection, and maintenance, as well as in multiple disease-related processes such as migraine, various cancers, and bladder hypersensitive disorders. Although no KO/CKO mouse model-specific findings were emphasized in the given references, the studies overall highlight the significance of TRPM8 in these biological and disease-related contexts, suggesting its potential as a therapeutic target in these areas.

References:

1. Dussor, Greg, Cao, Yu-Qing. 2016. TRPM8 and Migraine. In Headache, 56, 1406-1417. doi:10.1111/head.12948. https://pubmed.ncbi.nlm.nih.gov/27634619/

2. Voets, T, Owsianik, G, Nilius, B. . TRPM8. In Handbook of experimental pharmacology, , 329-44. doi:. https://pubmed.ncbi.nlm.nih.gov/17217067/

3. Izquierdo, Carolina, Martín-Martínez, Mercedes, Gómez-Monterrey, Isabel, González-Muñiz, Rosario. 2021. TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. In International journal of molecular sciences, 22, . doi:10.3390/ijms22168502. https://pubmed.ncbi.nlm.nih.gov/34445208/

4. Wu, Zunan, Peng, Shuai, Huang, Wensha, Yu, Xiaoyun, Shen, Lei. 2024. The Role and Function of TRPM8 in the Digestive System. In Biomolecules, 14, . doi:10.3390/biom14070877. https://pubmed.ncbi.nlm.nih.gov/39062591/

5. Ochoa, Sara V, Casas, Zulma, Albarracín, Sonia L, Sutachan, Jhon Jairo, Torres, Yolima P. 2023. Therapeutic potential of TRPM8 channels in cancer treatment. In Frontiers in pharmacology, 14, 1098448. doi:10.3389/fphar.2023.1098448. https://pubmed.ncbi.nlm.nih.gov/37033630/

6. Pertusa, María, Solorza, Jocelyn, Madrid, Rodolfo. 2023. Molecular determinants of TRPM8 function: key clues for a cool modulation. In Frontiers in pharmacology, 14, 1213337. doi:10.3389/fphar.2023.1213337. https://pubmed.ncbi.nlm.nih.gov/37388453/

7. Aizawa, Naoki, Fujita, Tomoe. . The TRPM8 channel as a potential therapeutic target for bladder hypersensitive disorders. In Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi, 58, 11-21. doi:10.1540/jsmr.58.11. https://pubmed.ncbi.nlm.nih.gov/35354708/

8. Liu, Yuqian, Mikrani, Reyaj, He, Yanjun, Li, Cuican, Zhou, Xiaohui. 2020. TRPM8 channels: A review of distribution and clinical role. In European journal of pharmacology, 882, 173312. doi:10.1016/j.ejphar.2020.173312. https://pubmed.ncbi.nlm.nih.gov/32610057/