α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons

Abstract

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.

Neuroprotective, Neurogenic, and Amyloid Beta Reducing Effect of a Novel Alpha 2-Adrenoblocker, Mesedin, on Astroglia and Neuronal Progenitors upon Hypoxia and Glutamate Exposure

“…The effect of mesedin on the cholinergic activity and synaptic formation and maturation via an increase in ChAT and PSD95 expression may be at least partially explained by the α2 blockade induced increase of neural growth factor, that in turn is capable of enhancing ChAT and PSD95 production [ 54 , 55 ]. The α2 blockade by mesedin appears also to increase the expression of the pre-synaptic marker of exocytosis, synaptophysin, in neurons, and astroglia from 3×Tg-AD APC, which is logically concordant with the notion that α2 agonists are involved in inhibition of synaptic vesicle exocytosis in hippocampal neurons [ 56 ]. Taking into account the synaptogenic function of astrocytes [ 57 ], it can be suggested that α2 blockade by mesedin provides the improvement of this function, acting (i) directly via its synaptophysin/PSD95-increasing effect on the neurons, and (ii) indirectly through the protection of astrocytes against hypoxia and Aβ cytotoxicity.…”

Dexmedetomidine Protects Against Traumatic Brain Injury-Induced Acute Lung Injury in Mice

“…It is well known that Dex is a highly selective α 2 adrenergic receptor agonist. Therefore, we used Atip, an α 2 adrenergic receptor antagonist, to determine whether the protective effect of Dex on TBI-induced ALI in mice was related to its α 2 adrenergic receptor activating effect [ 31 ]. Results showed that Atip partly reversed serum HMGB1 levels and the expression of RAGE in lung tissues.…”

Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems

“…Being mostly G i -coupled, α2 adrenergic receptor activation is generally inhibitory, reducing cAMP synthesis, and causing opening of K + channels or inhibition of AMPA glutamate-gated channels (Aghajanian and VanderMaelen, 1982 ; Franks, 2008 ; Ishii et al, 2008 ; Lur and Higley, 2015 ). Most often, the α2 receptor class is found on neuronal terminals, including noradrenergic LC axons, but also on many other types of neuron, and acts to reduce transmitter release (Matsuo et al, 2003 ; Shields et al, 2009 ; Hara et al, 2016 ). The prototype drug clonidine also produces sedation and works through these α2 adrenergic receptors, but activates other types of metabotropic receptor too.…”