Membrane-mediated anesthesia or anaesthesia (UK) is a mechanism of action that involves an anesthetic exerting its effects through the lipid membrane. Established mechanism exists for both general and local anesthetics.[1][2] The anesthetic binding site is within ordered lipids and binding disrupts the function of the ordered lipid. See Theories of general anaesthetic action for a broader discussion of purely theoretical mechanisms.

General anesthetics

Inhaled anesthetics partition into the membrane and disrupt the function of ordered lipids.[3] Membranes, like proteins are composed of ordered and disordered regions.[4] The ordered region of the membrane contain a palmitate binding site that drives the association of palmitoylated proteins to clusters of GM1 lipids (sometimes referred to as lipid rafts). Palmitate's binding to lipid rafts regulates the affinity of most proteins to lipid rafts.[5]

Anesthetic (orange) is shown competing with the palmitates (blue) of a palmitoylated protein (green). The displacement of the protein from the ordered lipids in the membrane (grey) renders the protein anesthetic sensitivity. The palmitate site is selective and structured similar to a protein despite being comprised of lipids

Inhaled anesthetics partition into the lipid membrane and disrupt the binding of palmitate to GM1 lipids (see figure). The anesthetic binds to a specific palmitate site nonspecifically. The clusters of GM1 lipids persist, but they lose their ability to bind palmitoylated proteins.[6]

PLD2

Phospholipase D2 (PLD2) is a palmitoylated protein that is activated by substrate presentation.[7] Anesthetics cause PLD2 to move from GM1 lipids , where it lacks access to its substrate, to a PIP2 domain which has abundant PLD2 substrate.[8] Animals with genetically depleted PLD2 were significantly resistant to anesthetics. The anesthetics xenon, chloroform, isofluorane, and propofol all activate PLD in cultured cells.

TREK-1

Twik-related potassium channel (TREK-1) is localized to ordered lipids through its interaction with PLD2. Displacement of the complex from GM1 lipids causes the complex to move to clusters. The product of PLD2, phosphatidic acid (PA) directly activates TREK-1.[9] The anesthetic sensitivity of TREK-1 was shown to be through PLD2 and the sensitivity could be transferred to TRAAK, an otherwise anesthetic insensitive channel.[10]

Endocytosis

Endocytosis helps regulate the time an ion channel spends on the surface of the membrane. GM1 lipids are the site of endocytosis. The anesthetics hydroxychloroquine, tetracain, and lidocaine blocked entry of palmitoylated protein into the endocytic pathway.[11] By blocking access to GM1 lipids anesthetics block access to endocytosis through a membrane-mediated mechanism.

Local anesthetics

Local anesthetics disrupt ordered lipid domains and this can cause PLD2 to leave a lipid raft.[12] They also disrupt protein interactions with PIP2.[13]

History

More than 100 years ago, a unifying theory of anesthesia was proposed based on the oil partition coefficient. In the 70s this concept was extended to the disruption of lipid partitioning.[14] Partitioning itself is an integral part of forming the ordered domains in the membrane, and the proposed mechanism is very close to the current thinking, but the partitioning itself is not the target of the anesthetics. At clinical concentration, the anesthetics do not inhibit lipid partitioning.[15] Rather they inhibit the order within the partition and or compete for the palmitate binding site. Nonetheless, several of the early conceptual ideas about how disruption of lipid partitioning could affect an ion channel, have merit.

References

  1. ↑ Pavel, MA; Petersen, EN; Wang, H; Lerner, RA; Hansen, SB (16 June 2020). "Studies on the mechanism of general anesthesia". Proceedings of the National Academy of Sciences of the United States of America. 117 (24): 13757–13766. Bibcode:2020PNAS..11713757P. doi:10.1073/pnas.2004259117. PMC 7306821. PMID 32467161.
  2. ↑ Pavel, MA; Chung, HW; Petersen, EN; Hansen, SB (October 2019). "Polymodal Mechanism for TWIK-Related K+ Channel Inhibition by Local Anesthetic". Anesthesia and Analgesia. 129 (4): 973–982. doi:10.1213/ANE.0000000000004216. PMID 31124840. S2CID 163166750.
  3. ↑ Pavel, MA; Petersen, EN; Wang, H; Lerner, RA; Hansen, SB (16 June 2020). "Studies on the mechanism of general anesthesia". Proceedings of the National Academy of Sciences of the United States of America. 117 (24): 13757–13766. Bibcode:2020PNAS..11713757P. doi:10.1073/pnas.2004259117. PMC 7306821. PMID 32467161.
  4. ↑ Sezgin, E; Levental, I; Mayor, S; Eggeling, C (June 2017). "The mystery of membrane organization: composition, regulation and roles of lipid rafts". Nature Reviews. Molecular Cell Biology. 18 (6): 361–374. doi:10.1038/nrm.2017.16. PMC 5500228. PMID 28356571.
  5. ↑ Levental, I; Lingwood, D; Grzybek, M; Coskun, U; Simons, K (21 December 2010). "Palmitoylation regulates raft affinity for the majority of integral raft proteins". Proceedings of the National Academy of Sciences of the United States of America. 107 (51): 22050–4. Bibcode:2010PNAS..10722050L. doi:10.1073/pnas.1016184107. PMC 3009825. PMID 21131568.
  6. ↑ Petersen, EN; Pavel, MA; Wang, H; Hansen, SB (1 January 2020). "Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1862 (1): 183091. doi:10.1016/j.bbamem.2019.183091. PMC 6907892. PMID 31672538.
  7. ↑ Petersen, EN; Chung, HW; Nayebosadri, A; Hansen, SB (15 December 2016). "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D." Nature Communications. 7: 13873. Bibcode:2016NatCo...713873P. doi:10.1038/ncomms13873. PMC 5171650. PMID 27976674.
  8. ↑ Petersen, EN; Pavel, MA; Wang, H; Hansen, SB (1 January 2020). "Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1862 (1): 183091. doi:10.1016/j.bbamem.2019.183091. PMC 6907892. PMID 31672538.
  9. ↑ Comoglio, Y; Levitz, J; Kienzler, MA; Lesage, F; Isacoff, EY; Sandoz, G (16 September 2014). "Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid". Proceedings of the National Academy of Sciences of the United States of America. 111 (37): 13547–52. Bibcode:2014PNAS..11113547C. doi:10.1073/pnas.1407160111. PMC 4169921. PMID 25197053.
  10. ↑ Pavel, MA; Petersen, EN; Wang, H; Lerner, RA; Hansen, SB (16 June 2020). "Studies on the mechanism of general anesthesia". Proceedings of the National Academy of Sciences of the United States of America. 117 (24): 13757–13766. Bibcode:2020PNAS..11713757P. doi:10.1073/pnas.2004259117. PMC 7306821. PMID 32467161.
  11. ↑ Yuan, Z; Pavel, MA; Wang, H; Kwachukwu, JC; Mediouni, S; Jablonski, JA; Nettles, KW; Reddy, CB; Valente, ST; Hansen, SB (14 September 2022). "Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture". Communications Biology. 5 (1): 958. doi:10.1038/s42003-022-03841-8. PMC 9472185. PMID 36104427.
  12. ↑ Pavel, MA; Chung, HW; Petersen, EN; Hansen, SB (October 2019). "Polymodal Mechanism for TWIK-Related K+ Channel Inhibition by Local Anesthetic". Anesthesia and Analgesia. 129 (4): 973–982. doi:10.1213/ANE.0000000000004216. PMID 31124840. S2CID 163166750.
  13. ↑ Yuan, Z; Pavel, MA; Wang, H; Kwachukwu, JC; Mediouni, S; Jablonski, JA; Nettles, KW; Reddy, CB; Valente, ST; Hansen, SB (14 September 2022). "Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture". Communications Biology. 5 (1): 958. doi:10.1038/s42003-022-03841-8. PMC 9472185. PMID 36104427.
  14. ↑ Trudell, JR (January 1977). "A unitary theory of anesthesia based on lateral phase separations in nerve membranes". Anesthesiology. 46 (1): 5–10. doi:10.1097/00000542-197701000-00003. PMID 12686. S2CID 24107213.
  15. ↑ Pavel, MA; Petersen, EN; Wang, H; Lerner, RA; Hansen, SB (16 June 2020). "Studies on the mechanism of general anesthesia". Proceedings of the National Academy of Sciences of the United States of America. 117 (24): 13757–13766. Bibcode:2020PNAS..11713757P. doi:10.1073/pnas.2004259117. PMC 7306821. PMID 32467161.
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