Mechanistic insights into volatile anesthetic modulation of K2P channels
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 funct...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/59839 |
| _version_ | 1818019332155768832 |
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| author | Aboubacar Wague Thomas T Joseph Kellie A Woll Weiming Bu Kiran A Vaidya Natarajan V Bhanu Benjamin A Garcia Crina M Nimigean Roderic G Eckenhoff Paul M Riegelhaupt |
| author_facet | Aboubacar Wague Thomas T Joseph Kellie A Woll Weiming Bu Kiran A Vaidya Natarajan V Bhanu Benjamin A Garcia Crina M Nimigean Roderic G Eckenhoff Paul M Riegelhaupt |
| author_sort | Aboubacar Wague |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:50:53Z |
| format | Article |
| id | doaj.art-7e11d5322d4c418d8767b99777b16d8b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:50:53Z |
| publishDate | 2020-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7e11d5322d4c418d8767b99777b16d8b2022-12-22T02:05:12ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.59839Mechanistic insights into volatile anesthetic modulation of K2P channelsAboubacar Wague0Thomas T Joseph1Kellie A Woll2Weiming Bu3Kiran A Vaidya4Natarajan V Bhanu5Benjamin A Garcia6Crina M Nimigean7https://orcid.org/0000-0002-6254-4447Roderic G Eckenhoff8Paul M Riegelhaupt9https://orcid.org/0000-0001-8593-2605Department of Anesthesiology, Weill Cornell Medical College, New York City, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United StatesDepartment of Anesthesiology, Weill Cornell Medical College, New York City, United StatesEpigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesEpigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Anesthesiology, Weill Cornell Medical College, New York City, United States; Department of Physiology and Biophysics, Weill Cornell Medical College, New York City, United States; Department of Biochemistry, Weill Cornell Medical College, New York City, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United StatesDepartment of Anesthesiology, Weill Cornell Medical College, New York City, United StatesK2P 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.https://elifesciences.org/articles/59839K2PTREK1isofluraneanesthetic |
| spellingShingle | Aboubacar Wague Thomas T Joseph Kellie A Woll Weiming Bu Kiran A Vaidya Natarajan V Bhanu Benjamin A Garcia Crina M Nimigean Roderic G Eckenhoff Paul M Riegelhaupt Mechanistic insights into volatile anesthetic modulation of K2P channels eLife K2P TREK1 isoflurane anesthetic |
| title | Mechanistic insights into volatile anesthetic modulation of K2P channels |
| title_full | Mechanistic insights into volatile anesthetic modulation of K2P channels |
| title_fullStr | Mechanistic insights into volatile anesthetic modulation of K2P channels |
| title_full_unstemmed | Mechanistic insights into volatile anesthetic modulation of K2P channels |
| title_short | Mechanistic insights into volatile anesthetic modulation of K2P channels |
| title_sort | mechanistic insights into volatile anesthetic modulation of k2p channels |
| topic | K2P TREK1 isoflurane anesthetic |
| url | https://elifesciences.org/articles/59839 |
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