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  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 such as AP-1, CREB, c-Fos, c-Jun, Egr-1, and Elk-1. Potential delayed response genes such as interleukin-8 and calcitonin gene related peptide (CGRP) have been identified. TRPM3-induced gene transcription is controlled by epigenetic regulators, including the histone acetyltransferases CBP and p300, as well as proteins of the bromodomain and extra terminal domain (BET) family. 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.