TREK1

TREK-1 (TWIK-related K+ channel 1) is a member of the two-pore-domain potassium (K2P) channel family. It is encoded by the human KCNK2 gene and forms background potassium leak channels that help set the resting membrane potential and regulate neuronal excitability.

Structure and assembly: Each TREK-1 subunit contains two pore-forming P-loop domains and four transmembrane segments. Four subunits assemble to form a functional tetrameric channel that conducts K+ ions across the cell membrane.

Expression: TREK-1 is broadly expressed in the nervous system, with notable abundance in the cortex and hippocampus, and is also detected in heart, skeletal muscle, and other tissues.

Regulation: It is activated by mechanical stretch and membrane tension, as well as by temperature changes and by certain lipid mediators such as polyunsaturated fatty acids. The channel is modulated by intracellular signaling, including GPCR pathways, phosphorylation, and changes in pH. It is a target of various anesthetics that enhance its activity.

Physiological and clinical relevance: In neurons, TREK-1 shapes excitability and contributes to neuroprotection during ischemic stress. In animal models, deletion of TREK-1 produces antidepressant-like behavior, whereas pharmacological blockade or inhibition can have mood-enhancing effects, making TREK-1 a potential target for mood disorders. It also participates in nociception and pain signaling and may influence anesthesia responses.

Research and tools: TREK-1 is studied using genetic knockouts, selective antagonists and modulators, and peptide inhibitors such as spadin, which reduces TREK-1 activity and has been explored for antidepressant-like effects.