K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

Yin Yao Dong(University of Oxford), A.C.W. Pike(University of Oxford), Alexandra Mackenzie(University of Oxford), Conor McClenaghan(University of Oxford), Prafulla Aryal(University of Oxford), Liang Dong(University of Oxford), Andrew Quigley(University of Oxford), Mariana Grieben(University of Oxford), S. Goubin(University of Oxford), Shubhashish Mukhopadhyay(University of Oxford), G.F. Ruda(University of Oxford), Michael V. Clausen(University of Oxford), Lishuang Cao(Pfizer (United Kingdom)), Paul E. Brennan(University of Oxford), N. Burgess-Brown(University of Oxford), Mark S.P. Sansom(University of Oxford), Stephen J. Tucker(University of Oxford), Elisabeth P. Carpenter(University of Oxford)
Science
March 12, 2015
10.1126/science.1261512
Cited by 311Open Access
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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.

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