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Programme
Contents
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The K2P channels are highly conserved from C. elegans to humans. They are structurally distinct from other K+ channel family members, with four transmembrane segments and 2P domains in tandem. K2P channels are homo- or hetero-dimers that play a dominant role in cell electrogenesis, controlling the resting membrane potential and the action potential duration.
The K2P channel TREK-1 is predominantly expressed in the central and peripheral nervous system, with a particularly strong expression during early development. TREK-1 is activated by membrane stretch as well as cell swelling. Mechanical force is transmitted directly to the channel via the lipid bilayer. Moreover, intracellular acidosis strongly sensitizes TREK-1 to membrane stretch, leading to channel opening at atmospheric pressure.
TREK-1 is reversibly opened by polyunsaturated fatty acids, including arachidonic acid (AA). Activation of TREK-1 by AA in the excised patch configuration indicates that the effect is direct by interacting either with the channel protein or by partitioning into the lipid bilayer. Additionally, TREK-1 channel activity is reversibly stimulated by volatile general anaesthetics including halothane.
The recent invalidation of TREK-1 in a mouse model demonstrates that this K+ channel is important for neuroprotection against epilepsy and ischemia. Furthermore, TREK-1 -/- mice are also more resistant to volatile general anaesthetics, indicating a key role for TREK-1 in the mechanism of general anaesthesia.
Mutagenesis studies have demonstrated that the cytosolic carboxy terminal domain of TREK-1 plays a key role in TREK-1 gating. Protonation of a key residue in this region, E306, leads to channel activation. Interaction of the carboxy terminal domain of TREK-1 with the inner leaflet phospholipids including PIP2 is critical for channel activity and is controlled by a cluster of cationic residues. Conversely, down-modulation of TREK-1 is achieved by receptor- coupled protein kinase A phosphorylation of residue S333.
In conclusion, the TREK channels are polymodal K+ channels that integrate multiple physical and chemical stimuli.