Abstract
K2P potassium channels are known to be modulated by volatile anesthetic (VA) drugs and play important roles in clinically relevant effects that accompany general anesthesia. Here, we utilize a photoaffinity analog of the VA isoflurane to identify a VA-binding site in the TREK1 K2P channel. The functional importance of the identified site was validated by mutagenesis and biochemical modification. Molecular dynamics simulations of TREK1 in the presence of VA found multiple neighboring residues on TREK1 TM2, TM3, and TM4 that contribute to anesthetic binding. The identified VA-binding region contains residues that play roles in the mechanisms by which heat, mechanical stretch, and pharmacological modulators alter TREK1 channel activity and overlaps with positions found to modulate TASK K2P channel VA sensitivity. Our findings define molecular contacts that mediate VA binding to TREK1 channels and suggest a mechanistic basis to explain how K2P channels are modulated by VAs.
Highlights
Tandem pore (K2P) potassium channels are a group of physiologically important K+ leak channels that modulate cellular resting membrane potential to control excitability (Enyedi and Czirjak, 2010)
Azi-isoflurane has been shown to retain the anesthetic effects of isoflurane in animals, and we first sought to ensure that the chemical modifications present in the azi-isoflurane compound would not alter the effect of this drug on the TREK1 channel
The drTREK1 channel has previously been shown to respond to multiple TREK1 modulatory cues including arachidonic acid and mechanical stretch (Brohawn et al, 2014b), and we found no evidence of differences in the functional behavior of the two orthologues with respect to modulation by azi-isoflurane, temperature, or the TREK1 activator BL1249 (Figure 3 and Figure 3—figure supplement 1), the modulatory cues explored in our study
Summary
Tandem pore (K2P) potassium channels are a group of physiologically important K+ leak channels that modulate cellular resting membrane potential to control excitability (Enyedi and Czirjak, 2010). Systemic effects of VA administration have been directly linked to K2P channel activity, including a role for carotid body TASK channels in mediating VA-induced respiratory depression (Cotten, 2013; Chokshi et al, 2015) and for TREK1 channels in the vasodilatory and neuroprotective effects of both polyunsaturated fatty acids and VAs (Blondeau et al, 2007; Tong et al, 2014). Initial evidence for a VA-induced potassium leak current was found in molluscan pacemaker neurons, an activity subsequently determined to be mediated by a member of the TASK K2P subfamily
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