Regulation of Two-pore Domain K plus Channels by Natural Effectors and Pharmacological Agents
ACTA PHYSIOLOGICA 221 (2017) 64-64
The structural movement of the TM4 segment during pore gating in TREK1 channels
ACTA PHYSIOLOGICA 219 (2017) 80-80
Functional annotation of ion channel structures by molecular simulation
Structure Cell Press 24:12 (2016) 2207-2216
Abstract:
Ion channels play key roles in cell membranes, and recent advances are yielding an increasing number of structures. However, their functional relevance is often unclear and better tools are required for their functional annotation. In sub-nanometer pores such as ion channels, hydrophobic gating has been shown to promote dewetting to produce a functionally closed (i.e. non-conductive) state. Using the serotonin receptor (5-HT3R) structure as an example, we demonstrate the use of molecular dynamics to aid the functional annotation of channel structures via simulation of the behavior of water within the pore. Three increasingly complex simulation analyses are described: water equilibrium densities; single ion free energy profiles; and computational electrophysiology. All 3 approaches correctly predict the 5-HT3R crystal structure to represent a functionally closed (i.e. non-conductive) state. We also illustrate application of water equilibrium density simulations to annotate to different conformational states of a glycine receptor.Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states.
Journal of General Physiology Rockefeller University Press 147:6 (2016) 497-505
Abstract:
The TREK subfamily of two-pore domain (K2P) K+ channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals.A non-canonical voltage-sensing mechanism controls gating in K2P K(+) channels
Cell Cell Press 164:5 (2016) 937-949