Read the article in Science (Open Access): K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac
Abstract -- Reprint -- Full text
KCNK10, also known as TREK-2, is a two-pore domain (K2P) potassium channel, found in the plasma membranes of neuronal cells. It provides a background leak current and is regulated by diverse stimuli including physical factors such as mechanical stretch, voltage and temperature, natural ligands such as polyunsaturated acids arachidonic acid and both intra- and extracellular pH [1-4]. Its activity can also be modulated by a variety of pharmacological agents such as volatile anesthetics , neuroprotective drugs  and antidepressants such as fluoxetine (Prozac) [7, 8] in vitro. Such diverse regulation allows these channels to couple cellular electrical activity to a remarkable variety of signaling pathways and consequently they represent important targets in pharmacology [9-11].
Here we present a structure of TREK-2 in the up state to 3.4Å resolution. TREK-2 has a classic K2P channel fold formed from a disulphide-linked dimer. Each monomer has two pore forming domains, giving an overall pseudo four-fold symmetry. K2P channels have four transmembrane helices (M1 to M4), with cytoplasmic N- and C-termini. The M1 helix is connected at an extracellular cap domain with two helices, a disulphide at the apex and a domain swap. This is followed by a pore helix and pore filter sequence, helices M2 and M3, a second pore helix and pore filter sequence, followed by the M4 helix. The pore filter provides a series of carbonyls which coordinate the potassium ions. In this structure we observed four potassium ions in the filter.
In the 4BW5 structure we observed an upwards movement of the M2 - M4 helices on the cytoplasmic side of the membrane, relative to the arrangement seen in the 'down' state. This structure could represent a stretch activated state of TREK-2, where mechanical force applied to the lipid membrane leads to an upward movement in transmembrane helices M2-M4 into this up conformation. In this conformation, the C-terminal portion of helix M4 from one protomer packs tightly against the M2 helix from the adjacent protomer. As a result, no side fenestrations are observed between the transmembrane helices and the inner vestibule.
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