- The Transient Receptor Potential Melastatin (TRPM) channel subfamily is a diverse group within the TRP superfamily, playing essential roles in ion homeostasis, sensory transduction, cellular metabolism, and cell proliferation.
- TRPM channels are non-selective cation channels with variable permeability to calcium (Ca²⁺), sodium (Na⁺), and in some cases, magnesium (Mg²⁺) and zinc (Zn²⁺). They are activated by a wide array of stimuli including temperature, oxidative stress, osmotic changes, intracellular signaling molecules, and second messengers.
- Due to their broad physiological roles, TRPM channels are key regulators of sensory perception, cellular stress responses, and metabolic balance.
- The TRPM subfamily consists of eight members, TRPM1 through TRPM8, each with distinct functional characteristics. These channels are structurally similar, featuring six transmembrane domains with a pore region between the fifth and sixth segments, and large intracellular N- and C-terminal domains that mediate interactions with regulatory proteins and signaling pathways. Unlike other TRP channels, TRPM proteins often lack ankyrin repeat domains, which distinguishes them from the TRPC and TRPV families.
- TRPM1 was initially identified as a tumor suppressor gene in melanoma and is highly expressed in retinal bipolar cells, where it plays a critical role in visual signal transduction. Mutations in TRPM1 are associated with congenital stationary night blindness. TRPM2 is unique for its activation by oxidative stress and ADP-ribose, making it a redox-sensitive channel involved in cell death, inflammation, and immune responses. TRPM3 is involved in nociception and thermosensation, particularly in detecting noxious heat. TRPM4 and TRPM5 are impermeable to Ca²⁺ but are activated by intracellular Ca²⁺ and function as monovalent cation channels. They are involved in insulin secretion, chemosensory signaling (especially in taste cells), and immune cell activation.
- TRPM6 and TRPM7 are distinctive among ion channels for having both ion channel and kinase domains (referred to as “chanzyme” properties). These channels are critical for Mg²⁺ homeostasis and are involved in regulating cell proliferation, migration, and survival. Deficiencies in TRPM6 cause hypomagnesemia with secondary hypocalcemia, a rare but serious genetic disorder. Finally, TRPM8 is a well-characterized cold and menthol receptor, involved in thermosensation and pain modulation, making it a promising target in treating chronic pain and inflammation.
- Functionally, TRPM channels are expressed widely in both excitable and non-excitable tissues and are integral to diverse physiological processes such as taste perception, temperature regulation, vision, immune defense, epithelial ion transport, and cell cycle control. Given their broad distribution and functional importance, TRPM channels have been implicated in various pathological conditions including cancer, cardiovascular diseases, neurodegeneration, metabolic disorders, and inflammatory diseases.
