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TitleStructural interplay of anesthetics and paralytics on muscle nicotinic receptors.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3169, Year 2023
Publish dateJun 1, 2023
AuthorsUmang Goswami / Md Mahfuzur Rahman / Jinfeng Teng / Ryan E Hibbs /
PubMed AbstractGeneral anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and ...General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.
External linksNat Commun / PubMed:37264005 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 2.9 Å
Structure data

28576

8esk

EMDB-28576, PDB-8esk:
Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with rocuronium, resting-like state
Method: EM (single particle) / Resolution: 2.9 Å

28826

8f2s

EMDB-28826, PDB-8f2s:
Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with rocuronium, pore-blocked state
Method: EM (single particle) / Resolution: 2.9 Å

28892

8f6y

EMDB-28892, PDB-8f6y:
Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with etomidate, desensitized-like state
Method: EM (single particle) / Resolution: 2.79 Å

28893

8f6z

EMDB-28893, PDB-8f6z:
Cryo-EM structure of Torpedo nicotinic acetylcholine receptor in complex with succinylcholine, desensitized-like state
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-RBR:
rocuronium

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-DD9:
nonane / Nonane

ChemComp-V8D:
Etomidate / Etomidate

ChemComp-CHT:
CHOLINE ION / Choline

ChemComp-HOH:
WATER / Water

ChemComp-SCK:
2,2'-[(1,4-DIOXOBUTANE-1,4-DIYL)BIS(OXY)]BIS(N,N,N-TRIMETHYLETHANAMINIUM)

Source
  • tetronarce californica (Pacific electric ray)
  • Pacific electric ray (Pacific electric ray)
KeywordsTRANSPORT PROTEIN/INHIBITOR / acetylcholine receptor / nicotinic receptor / Torpedo / Cys-loop receptor / ion channel / muscle-type nicotinic receptor / TRANSPORT PROTEIN-INHIBITOR complex / Neuromuscular Blocker / Inhibitor / General anesthetic

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