TRPM4

TRPM4, or transient receptor potential melastatin 4, is a member of the TRP channel family, subfamily TRPM. It forms a tetrameric, nonselective cation channel that is activated by increases in intracellular calcium. The channel is permeable to monovalent cations such as sodium and potassium, but it has little to no permeation by calcium itself, so it tends to influence membrane potential rather than carry calcium ions through.

Activation and regulation of TRPM4 occur when cytosolic Ca2+ rises to micromolar levels. The channel can be modulated by phosphoinositides and other intracellular signals, and its activity leads to membrane depolarization. This depolarization can enhance the driving force for calcium entry through other channels, linking TRPM4 to excitation and signaling in various cell types. TRPM4 is generally considered voltage-insensitive, though its current can produce outward-rectifying or complex voltage behaviors depending on cellular context.

Expression of TRPM4 is broad, including heart, brain, immune cells, and vascular tissues. In the heart, it contributes to the conduction system and has been associated with familial cardiac conduction disease when pathogenic variants are present. In the nervous system and in vascular tissues, TRPM4 participates in cellular excitability, signaling, and regulation of vascular tone. Research has also explored its role in pathological conditions such as cerebral edema after ischemia and inflammatory responses.

Genetically, the TRPM4 gene encodes the channel protein. Pathogenic variants have been linked to cardiac conduction block and related arrhythmias, often with autosomal dominant inheritance patterns.

Pharmacologically, 9-phenanthrol is a commonly used TRPM4 inhibitor in experimental studies, though specificity is not absolute and off-target effects can occur at higher concentrations.