Stimulus-Transcription Coupling of TRPM3 Channels: A Signaling Pathway from the Plasma Membrane to the Nucleus

Transient receptor potential melastatin-3 (TRPM3) channels are cation channels activated by heat and chemical ligands. TRPM3 regulates heat sensation, secretion, neurotransmitter release, iris constriction, and tumor promotion. Stimulation of TRPM3 triggers an influx of Ca²⁺ ions into the cells and the initiation of an intracellular signaling cascade. TRPM3 channels are regulated by phosphatidylinositol 4,5-bisphosphate, the βγ subunit of G-protein-coupled receptors, phospholipase C, and calmodulin. Extracellular signal-regulated protein kinase ERK1/2 and c-Jun N-terminal protein kinase (JNK) function as signal transducers. The signaling cascade is negatively regulated by the protein phosphatases MKP-1 and calcineurin and increased concentrations of Zn²⁺. Stimulation of TRPM3 leads to the activation of stimulus-responsive transcription factors controlled by epigenetic regulators. Potential delayed response genes encoding the pro-inflammatory regulators interleukin-8, calcitonin gene-related peptide, and the prostaglandin-synthesizing enzyme prostaglandin endoperoxide synthase-2 have been identified. Elucidating the TRPM3-induced signaling cascade provides insights into how TRPM3 stimulation alters numerous biochemical and physiological parameters within the cell and throughout the organism and offers intervention points for manipulating TRPM3 signaling and function.