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Altered surface trafficking of presynaptic cannabinoid type 1 receptor in and out synaptic terminals parallels receptor desensitization.

ABSTRACT: Presynaptic cannabinoid type 1 receptors (CB1Rs) are major mediators of retrograde synaptic plasticity at both excitatory and inhibitory synapses and participate in a plethora of physiological functions. Whether presynaptic receptors, such as CB1R, display functionally relevant movements at the surface of neuronal membranes is not known. We analyzed the lateral mobility of native CB1Rs in cortical neurons by using single-quantum dot imaging. We found that CB1Rs are highly mobile and rapidly diffuse in and out of presynapses. Agonist-induced desensitization correlated with a reduction in the fraction of surface CB1Rs and a drastic decrease in the membrane dynamic of the CB1Rs that remained at the presynaptic surface. Desensitization specifically excluded CB1Rs from synapses and increased the fraction of immobile receptors in the extrasynaptic compartment. The results suggest that decrease of mobility may be one of the core mechanisms underlying the desensitization of CB1R, the most abundant G protein-coupled receptor in the brain.

SUBMITTER: Mikasova L

PROVIDER: S-EPMC2584146 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Altered surface trafficking of presynaptic cannabinoid type 1 receptor in and out synaptic terminals parallels receptor desensitization.

Mikasova Lenka L Groc Laurent L Choquet Daniel D Manzoni Olivier J OJ

Proceedings of the National Academy of Sciences of the United States of America 20081117 47

Presynaptic cannabinoid type 1 receptors (CB1Rs) are major mediators of retrograde synaptic plasticity at both excitatory and inhibitory synapses and participate in a plethora of physiological functions. Whether presynaptic receptors, such as CB1R, display functionally relevant movements at the surface of neuronal membranes is not known. We analyzed the lateral mobility of native CB1Rs in cortical neurons by using single-quantum dot imaging. We found that CB1Rs are highly mobile and rapidly diff ...[more]

PMID: 19015531

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Project description:In presynaptic terminals, membrane-delimited Gi/o-mediated presynaptic inhibition is ubiquitous and acts via Gβγ to inhibit Ca2+ entry, or directly at SNARE complexes to inhibit Ca2+-dependent synaptotagmin-SNARE complex interactions. At CA1-subicular presynaptic terminals, 5-HT1B and GABAB receptors colocalize. GABAB receptors inhibit Ca2+ entry, whereas 5-HT1B receptors target SNARE complexes. We demonstrate in male and female rats that GABAB receptors alter Pr, whereas 5-HT1B receptors reduce evoked cleft glutamate concentrations, allowing differential inhibition of AMPAR and NMDAR EPSCs. This reduction in cleft glutamate concentration was confirmed by imaging glutamate release using a genetic sensor (iGluSnFR). Simulations of glutamate release and postsynaptic glutamate receptor currents were made. We tested effects of changes in vesicle numbers undergoing fusion at single synapses, relative placement of fusing vesicles and postsynaptic receptors, and the rate of release of glutamate from a fusion pore. Experimental effects of Pr changes, consistent with GABAB receptor effects, were straightforwardly represented by changes in numbers of synapses. The effects of 5-HT1B receptor-mediated inhibition are well fit by simulated modulation of the release rate of glutamate into the cleft. Colocalization of different actions of GPCRs provides synaptic integration within presynaptic terminals. Train-dependent presynaptic Ca2+ accumulation forces frequency-dependent recovery of neurotransmission during 5-HT1B receptor activation. This is consistent with competition between Ca2+-synaptotagmin and Gβγ at SNARE complexes. Thus, stimulus trains in 5-HT1B receptor agonist unveil dynamic synaptic modulation and a sophisticated hippocampal output filter that itself is modulated by colocalized GABAB receptors, which alter presynaptic Ca2+ In combination, these pathways allow complex presynaptic integration.SIGNIFICANCE STATEMENT Two G protein-coupled receptors colocalize at presynaptic sites, to mediate presynaptic modulation by Gβγ, but one (a GABAB receptor) inhibits Ca2+ entry whereas another (a 5-HT1B receptor) competes with Ca2+-synaptotagmin binding to the synaptic vesicle machinery. We have investigated downstream effects of signaling and integrative properties of these receptors. Their effects are profoundly different. GABAB receptors alter Pr leaving synaptic properties unchanged, whereas 5-HT1B receptors fundamentally change properties of synaptic transmission, modifying AMPAR but sparing NMDAR responses. Coactivation of these receptors allows synaptic integration because of convergence of GABAB receptor alteration on Ca2+ and the effect of this altered Ca2+ signal on 5-HT1B receptor signaling. This presynaptic convergence provides a novel form of synaptic integration.

Dataset Information

Altered surface trafficking of presynaptic cannabinoid type 1 receptor in and out synaptic terminals parallels receptor desensitization.

Publications

Altered surface trafficking of presynaptic cannabinoid type 1 receptor in and out synaptic terminals parallels receptor desensitization.

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