Molecular simulation studies of hydrophobic gating in nanopores and ion channels.
Biochemical Society Transactions Portland Press 43:2 (2015) 146-150
K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac
Science American Association for the Advancement of Science 347:6227 (2015) 1256-1259
Abstract:
TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
Frontiers in Physiology Frontiers 5 (2015) 525
Hydrophobic Gating in Ion Channels
Journal of Molecular Biology Elsevier 427:1 (2015) 121-130
Sensing the Electrochemical K+ Gradient: The Voltage Gating Mechanism in K2P Potassium Channels
Biophysical Journal Elsevier 108:2 (2015) 427a-428a