photoexcitation of rhodopsin to the opening of the TRP/TRPL channels. Although numerous activators of these channels such as phosphatidylinositol-4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) were known for years, a key factor mediating chemical coupling between PLC and TRP/TRPL channels remained a mystery until recently. It was found that breakdown of a lipid product of PLC cascade, diacylglycerol (DAG), by the enzyme diacylglycerol lipase, generates PUFAs that can activate TRP channels, thus initiating membrane depolarization in response to light. This mechanism of TRP channel activation may be well-preserved among other cell types where these channels perform various functions. Clinical significance Mutations in TRPs have been linked to neurodegenerative disorders, skeletal dysplasia, kidney disorders, and may play an important role in cancer. TRPs may make important therapeutic targets. There is significant clinical significance to TRPV1, TRPV2, TRPV3 and TRPM8’s role as thermoreceptors, and TRPV4 and TRPA1’s role as mechanoreceptors; reduction of chronic pain may be possible by targeting ion channels involved in thermal, chemical, and mechanical sensation to reduce their sensitivity to stimuli. For instance the use of TRPV1 agonists would potentially inhibit nociception at TRPV1, particularly in pancreatic tissue where TRPV1 is highly expressed. The TRPV1 agonist capsaicin, found in chili peppers, has been indicated to relieve neuropathic pain. TRPV1 agonists inhibit nociception at TRPV1 Role in cancer Altered expression of TRP proteins often leads to tumorigenesis, as reported for TRPV1, TRPV6, TRPC1, TRPC6, TRPM4, TRPM5, and TRPM8. TRPV1 and TRPV2 have been implicated in breast cancer. TRPV1 expression in aggregates found at endoplasmic reticulum or Golgi apparatus and/or surrounding these structures in breast cancer patients confer worse survival. TRPV2 is a potential biomarker and therapeutic target in triple negative breast cancer. TRPM family of ion channels are particularly associated with prostate cancer where TRPM2 (and its long noncoding RNA TRPM2-AS), TRPM4, and TRPM8 are overexpressed in prostate cancer associated with more aggressive outcomes. TRPM3 has been shown to promote growth and autophagy in clear cell renal cell carcinoma, TRPM4 is overexpressed in diffuse large B-cell lymphoma associated with poorer survival, while TRPM5 has oncogenic properties in melanoma. Role in inflammatory responses In addition to TLR4 mediated pathways, certain members of the family of the transient receptor potential ion channels recognize LPS. LPS-mediated activation of TRPA1 was shown in mice and Drosophila melanogaster flies. At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such