Perspectives on the Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K⁺ Channel 1). A Novel Therapeutic Target?

Abstract

Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating.

Arachidonic acid hyperpolarizes mesenchymal stromal cells from the human adipose tissue by stimulating TREK1 K+ channels

“…This inference was supported by the observation that 10-30 µM AA never elevated cytosolic Ca 2+ to the level ( Figure 1S) required for sufficient MSC hyperpolarization associated with the activation of Ca 2+ -gated K + channels [34]. On the other hand, AA-gated K + channels identified by us in MSCs were most closely related to the TREK-1 type by biophysical and pharmacological properties [18,[22][23][24]35], including their inhibition by spadin ( Figure 3(d,e)) and stimulation by BL 1249 (Figure 4), intracellular acidosis ( Figure 6(a)), and membrane stretch (Figure 6(b,c)).…”

GI‐530159, a novel, selective, mechanosensitive two‐pore‐domain potassium (K2P) channel opener, reduces rat dorsal root ganglion neuron excitability

“…There are a number of compounds that have been identified that activate TREK channels (see Mathie and Veale, ; Vivier et al ., ). Fenamate compounds, such as flufenamic acid, are non‐steroidal anti‐inflammatory drugs used clinically in the treatment of pain and are strong activators of TREK channels (Takahira et al ., ; Veale et al ., ) with flufenamic acid the most effective of these compounds (Veale et al ., ).…”

Deficiency of TREK‐1 potassium channel exacerbates secondary injury following spinal cord injury in mice

“…; Vivier et al . ). Accumulating studies have suggested that TREK‐1 has a key role in the cellular mechanisms of neurologic disorders such as depression, pain, cerebral ischemia, and experimental autoimmune encephalomyelitis (EAE) (Alloui et al .…”