Tandem pore domain (K2P) potassium channels modulate resting membrane potentials and shape cellular excitability. For the mechanosensitive subfamily of K2Ps, the composition of phospholipids within the bilayer strongly influences channel activity. To examine the molecular details of K2P lipid modulation, we solved cryo-EM structures of the TREK1 K2P channel bound to either the anionic lipid phosphatidic acid (PA) or the zwitterionic lipid phosphatidylethanolamine (PE). At the extracellular face of TREK1, a PA lipid inserts its hydrocarbon tail into a pocket behind the selectivity filter, causing a structural rearrangement that recapitulates mutations and pharmacology known to activate TREK1. At the cytoplasmic face, PA and PE lipids compete to modulate the conformation of the TREK1 TM4 gating helix. Our findings demonstrate two distinct pathways by which anionic lipids enhance TREK1 activity and provide a framework for a model that integrates lipid gating with the effects of other mechanosensitive K2P modulators.

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.

A cognitively intensive companion service course has been introduced to the main fall general chemistry class at Cornell University. For years 2015 and 2016, priority students (those from groups under-represented and economically disadvantaged) show respectively improvement of +0.67 and +0.51 standard deviations in final course grade compared to priority students not in the program. Non-priority students show respectively a +0.66 and +0.62 standard deviation improvement. Progressive improvement (as measured by higher than expected Final Exam scores than what would have been expected solely from a given student’s earlier Exam 1 score) demonstrates conclusively the service course’s role in the enhanced outcomes. Progressive retention (as measured by the following year fall semester’s organic chemistry exam scores compared to what would have been expected based on a given student’s general chemistry final exam score) demonstrates that, on the average, the earlier observed progressive improvement is significantly retained in a chemistry course one year later. Preliminary retention statistics suggest a significant increase in first year to second year retention. A meta analysis of results from previously reported chemistry service courses indicate that such performance gains are difficult to achieve and hence common elements of the few effective programs may be of high value to the STEM education community.

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