Department of Anesthesiology

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

TitleIsoflurane inhibits synaptic vesicle exocytosis through reduced Ca2+ influx, not Ca2+-exocytosis coupling.
Publication TypeJournal Article
Year of Publication2015
AuthorsBaumgart JP, Zhou Z-Y, Hara M, Cook DC, Hoppa MB, Ryan TA, Hemmings HC
JournalProc Natl Acad Sci U S A
Volume112
Issue38
Pagination11959-64
Date Published2015 Sep 22
ISSN1091-6490
KeywordsAction Potentials, Animals, Calcium, Exocytosis, GABAergic Neurons, Glutamates, Isoflurane, Kinetics, Presynaptic Terminals, Rats, Sprague-Dawley, Synaptic Vesicles
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 in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system.

DOI10.1073/pnas.1500525112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26351670
PubMed Central IDPMC4586856
Grant ListR01 GM058055 / GM / NIGMS NIH HHS / United States
R01 MH085783 / MH / NIMH NIH HHS / United States
R01GM58055 / GM / NIGMS NIH HHS / United States
R01MH085783 / MH / NIMH NIH HHS / United States
T32DA07274 / DA / NIDA NIH HHS / United States