Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca2+ influx, not Ca2+-exocytosis coupling

Proceedings of the National Academy of Sciences of the United States of America
Joel P BaumgartH C Hemmings

Abstract

Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca(2+) influx without significantly altering the Ca(2+) sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca(2+)]i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca(2+) ([Ca(2+)]e). Lowering external Ca(2+) to match the isoflurane-induced reduction in Ca(2+) entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca(2+) entry without significant direct effects on Ca(2+)-exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca(2+) influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration...Continue Reading

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Citations

Jul 2, 2016·Consciousness and Cognition·Oressia Zalucki, Bruno van Swinderen
Sep 14, 2017·Anesthesiology·Min-Ching Kuo, L Stan Leung
Jan 23, 2018·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Daixin Ye, Andrew Ewing
Feb 23, 2019·Journal of Neural Engineering·Amirali ToossiVivian K Mushahwar
Feb 23, 2019·The Journal of Pharmacology and Experimental Therapeutics·Cheng ZhouHugh C Hemmings
Oct 19, 2016·Anesthesiology·Andrew E Hudson, Kane O Pryor
Jun 20, 2020·Journal of Neural Engineering·Evan N NicolaiKip A Ludwig
Sep 1, 2019·Pharmacological Reviews·Nicholas DenommeGeorge A Mashour
May 11, 2020·Brain Stimulation·Kevin P ChengKip A Ludwig
Feb 29, 2020·Current Neuropharmacology·Xuechao HaoCheng Zhou
Apr 27, 2021·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Nikolaus BerndtAgustin Liotta
Jun 2, 2021·Brain Structure & Function·Simon GranakSaak V Ovsepian

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