Background: Evidence indicates that the anesthetic-sparing effects of α2-adrenergic receptor (AR) agonists involve α2A-AR heteroreceptors on nonadrenergic neurons. Since volatile anesthetics inhibit neurotransmitter release by reducing synaptic vesicle (SV) exocytosis, the authors hypothesized that α2-AR agonists inhibit nonadrenergic SV exocytosis and thereby potentiate presynaptic inhibition of exocytosis by isoflurane.
Methods: Quantitative imaging of fluorescent biosensors of action potential–evoked SV exocytosis (synaptophysin-pHluorin) and Ca2+ influx (GCaMP6) were used to characterize presynaptic actions of the clinically used α2-AR agonists dexmedetomidine and clonidine, and their interaction with isoflurane, in cultured rat hippocampal neurons.
Results: Dexmedetomidine (0.1 μM, n = 10) or clonidine (0.5 μM, n = 8) inhibited action potential–evoked exocytosis (54 ± 5% and 59 ± 8% of control, respectively; P < 0.001). Effects on exocytosis were blocked by the subtype-nonselective α2-AR antagonist atipamezole or the α2A-AR–selective antagonist BRL 44408 but not by the α2C-AR–selective antagonist JP 1302. Dexmedetomidine inhibited exocytosis and presynaptic Ca2+ influx without affecting Ca2+ coupling to exocytosis, consistent with an effect upstream of Ca2+–exocytosis coupling. Exocytosis coupled to both N-type and P/Q-type Ca2+ channels was inhibited by dexmedetomidine or clonidine. Dexmedetomidine potentiated inhibition of exocytosis by 0.7 mM isoflurane (to 42 ± 5%, compared to 63 ± 8% for isoflurane alone; P < 0.05).
Conclusions: Hippocampal SV exocytosis is inhibited by α2A-AR activation in proportion to reduced Ca2+ entry. These effects are additive with those of isoflurane, consistent with a role for α2A-AR presynaptic heteroreceptor inhibition of nonadrenergic synaptic transmission in the anesthetic-sparing effects of α2A-AR agonists.
Volatile anesthetics inhibit neurotransmitter release by reducing synaptic vesicle exocytosis
The authors tested the hypothesis that α2-adrenoceptor agonists potentiate presynaptic inhibition of nonadrenergic synaptic vesicle exocytosis by isoflurane
Using quantitative imaging of fluorescent biosensors of action potential–evoked synaptic vesicle exocytosis (synaptophysin-pHluorin) and Ca2+ influx (GCaMP6) in cultured rat hippocampal neurons, it was found that synaptic vesicle exocytosis was inhibited by both dexmedetomidine and clonidine in proportion to reduced Ca2+ entry
These effects were specifically due to activation of α2A-adrenoceptors and were additive with inhibition of release by isoflurane
Masato Hara, Zhen-Yu Zhou, Hugh C. Hemmings; α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons. Anesthesiology 2016;125(3):535-546. doi: https://doi.org/10.1097/ALN.0000000000001213.
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