Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

52-POS

Board 52

Voltage-dependent Gating and K

Block in Thetwik-1 K2P Channel.

Ehsan Nematian-Ardestani

, Marcus Schewe

, Thomas Baukrowitz

, Stephen J. Tucker

University of Oxford, Oxford, United Kingdom,

University of Kiel, Kiel, Germany.

Recently we have shown that nearly all K2P channels can be activated by voltage (Schewe et al,

2016 Cell 164:937-49). In that study, we also demonstrated that this voltage-dependent gating is

due to a ‘flux-gating’ mechanism located within the selectivity filter. However, the TWIK-1

channel appeared to be an exception to this general rule because it behaves primarily like a leak

channel. Here we now show that TWIK-1 can also exhibit voltage-dependent activation within

the physiological voltage range, but only with non-physiological permeant ions such as Rb

and

NH4

. Furthermore, we show that voltage-dependent activation with K

as the permeant ion can

also occur, but only at voltages beyond the physiological range. The low functional activity of

TWIK-1 appears to result from a combination of different possible mechanisms including post-

translational modification, rapid internalization and the existence of a hydrophobic barrier deep

within the inner pore. Our results now propose an additional mechanism, namely a strong

interaction of K

ions with the selectivity filter, that results in a block at physiological

concentrations (IC

~ 2.8 mM). This mechanism explains the unusual voltage-dependent

activation of TWIK-1 due to a strong inhibition by K

ions within the filter. These results

suggest that, like other K2P channels, TWIK-1 also possesses a voltage-dependent gate within

the selectivity filter; however, this mechanism appears exquisitely sensitive to the nature of the

permeant ion.