PT  - JOURNAL ARTICLE
AU  - Iris Speigel
AU  - Vanessa Osman
AU  - Hugh C Hemmings, Jr
TI  - Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons
AID  - 10.1101/2022.01.03.474845
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.03.474845
4099  - http://biorxiv.org/content/early/2022/01/03/2022.01.03.474845.short
4100  - http://biorxiv.org/content/early/2022/01/03/2022.01.03.474845.full
AB  - Volatile anesthetics alter presynaptic function including effects on Ca2+ influx and neurotransmitter release. These actions are proposed to play important roles in their pleiotropic neurophysiological effects including unconsciousness and amnesia. The nitric oxide and cyclic guanosine monophosphate (NO/cGMP) signaling pathway has been implicated in presynaptic mechanisms, and disruption of NO/cGMP signaling has been shown to alter sensitivity to volatile anesthetics in vivo. We investigated NO/cGMP signaling in relation to volatile anesthetic actions in cultured rat hippocampal neurons using pharmacological tools and genetically encoded biosensors of cGMP levels. Using the fluorescent biosensor cGull we found that electrical stmulation-evoked NMDA-type glutamate receptor-independent presynaptic cGMP transients were inhibited −33.2% by isoflurane (0.51 mM) and −23.8% by sevoflurane (0.57 mM) (p<0.0001) compared to a stimulation without anesthetic. Isoflurane and sevoflurane inhibition of stimulation-evoked increases in presynaptic Ca2+ concentration, measured with synaptophysin-GCaMP6f, and synaptic vesicle exocytosis, measured with synaptophysin-pHlourin, were reduced by in neurons expressing the cGMP scavenger sponGee. This reduction in anesthetic effect was recapitulated by inhibiting HCN channels, a cGMP-modulated effector that can facilitate glutamate release. We propose that volatile anesthetics depress presynaptic cGMP signaling and downstream effectors like HCN channels that are essential to presynaptic function and excitability. These findings identify a novel mechanism by which volatile anesthetics depress synaptic transmission via second messenger signaling involving the NO/cGMP pathway.Competing Interest StatementThe authors have declared no competing interest.