TREK Related Drug Discovery Products

Mammalian anesthetic-sensitive K⁺ channels' molecular origins have only lately been discovered. The new family of mammalian two-pore-domain K⁺ (K_2P) channel subunits (KCNK) includes these channels. These channels are referred to as "background" or "baseline" K⁺ channels because they are open throughout the whole voltage range. Clinical doses of volatile anesthetics can reversibly open the K_2P channels TREK-1 and TREK-2 instead of TRAAK. Recent research suggests that gaseous and other non-volatile general anesthetics can also open TREK-1. As a result, it has been suggested that TREK-1 is a key pharmacological target for general anesthetics.

Creative Biolabs can help you choose the best assays and products to meet your specific needs in TREK drug discovery. We can offer following services and products:

• TREK Assays
• Ion Channel Cell Lines
• Ion Channel Membranes
• Membrane Protein Tools

Overview of TREK

Increasing mechanical pressure placed on the cell membrane causes TREK channel activation. An external Mg²⁺ barrier at negative potentials and a slight voltage dependence are the causes of TREK-1's outward rectification in symmetric saline. The normal background or 'leak' activity of TREK-1 shows that it affects both the resting membrane excitability and the length of action potentials. Cellular volume influences TREK-1 at the level of the entire cell, with hyperosmolarity blocking the channel. The lipid bilayer allows for direct mechanical force transmission to the channel, and the cytoskeleton tonically inhibits TREK channel activation. For a 10°C temperature increase, heat reversibly opens TREK-1 with a roughly sevenfold increase in current amplitude. Lowering the intracellular pH causes the TREK-1 channel to open at atmospheric pressure by shifting the pressure-activation relationship in favor of positive values. A TREK mechano-gated channel becomes virtually constitutively active under intracellular acidosis.

Chemical stimulation also effectively opens TREK channels. Polyunsaturated fatty acids (PUFAs) reversibly activate TREK-1. The fact that PUFAs can activate TREK and TRAAK channels in excised patches suggests that the effect does not depend on the presence of an intact cell and instead results from either a direct interaction with the channel protein or as a result of partitioning into the lipid bilayer, which affects channel gating indirectly. In contrast to diacyl phospholipids, extracellular lysophospholipids, such as lysophosphatidylcholine (LPC), also open TREK channels.

Fig.1 Polymodal TREK-1 regulation.^1,2

TREK Drug Discovery

For a number of common simple anesthetics, TREK-1 plays a critical role in the induction of general anesthesia. The most conclusive evidence for this, at least for volatile anesthetics, comes from recent research on TREK-1 knockout mice. Additionally, it is obvious that opening of TREK-1 is crucial to shield neurons from both ischaemic and epileptic shocks. The functions of the other members of this fascinating family of ion channels in the general anesthetic state and in neuroprotection should become obvious when new K_2P channel transgenic mice become available.

References

1. Djillani, Alaeddine, et al. "Role of TREK-1 in health and disease, focus on the central nervous system." Frontiers in Pharmacology 10 (2019): 379.
2. Image retrieved from Figure 2 "Polymodal TREK-1 regulation." Djillani, et al. 2019, used under CC BY 4.0. The original image was modified by extracting and the title was changed to " Polymodal TREK-1 regulation.".