| Literature DB >> 25766236 |
Yin Yao Dong1, Ashley C W Pike1, Alexandra Mackenzie2, Conor McClenaghan3, Prafulla Aryal4, Liang Dong1, Andrew Quigley1, Mariana Grieben1, Solenne Goubin1, Shubhashish Mukhopadhyay1, Gian Filippo Ruda5, Michael V Clausen6, Lishuang Cao7, Paul E Brennan5, Nicola A Burgess-Brown1, Mark S P Sansom8, Stephen J Tucker9, Elisabeth P Carpenter10.
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.Entities:
Mesh：
Substances：
Year: 2015 PMID： 25766236 PMCID： PMC6034649 DOI： 10.1126/science.1261512
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728