Axonal CB1 Receptors Mediate Inhibitory Bouton Formation via cAMP Increase and PKA

Liang, Jian; Kruijssen, Dennis L.H.; Verschuuren, Aniek C. J.; Voesenek, Bas J. B.; Benavides, Feline F. W.; Gonzalez, Maria Sáez; Ruiter, Marvin; Wierenga, Corette J.

doi:10.1523/jneurosci.0851-21.2021

Cited by 15 publications

(10 citation statements)

References 135 publications

(215 reference statements)

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“…[62][63][64] Recent evidence links PKA activity to synapse formation. 65,66 What could be the function of PKA-induced PLPPR3-BASP1 complex at the synapse?…”

Section: Molecular Mechanism and Function Of Plppr3-basp1 Complex At ...mentioning

confidence: 99%

Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Kroon,

Bareesel,

Kirchner

et al. 2024

Preprint

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Phospholipid–phosphatase related protein 3 (PLPPR3, previously known as Plasticity Related Gene 2 or PRG2) belongs to a family of transmembrane proteins, highly expressed in neuronal development, which regulate critical growth processes in neurons. Prior work established crucial functions of PLPPR3 in axon guidance, filopodia formation and axon branching. However, little is known regarding the signaling events regulating PLPPR3 function. We identify here 26 high–confidence phosphorylation sites in the intracellular domain of PLPPR3 using mass spectrometry. Biochemical characterization established one of these — S351 — as a bona fide phosphorylation site of PKA. Experiments in neuronal cell lines suggest that phosphorylation of S351 does not regulate filopodia formation. Instead, it regulates binding to BASP1, a signaling molecule previously implicated in axonal growth and regeneration. Interestingly, both PLPPR3 intracellular domain and BASP1 enrich in presynapses in primary neurons. We propose that the presynaptic PLPPR3-BASP1 complex may function as novel signaling integrator at neuronal synapses.

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“…[62][63][64] Recent evidence links PKA activity to synapse formation. 65,66 What could be the function of PKA-induced PLPPR3-BASP1 complex at the synapse?…”

Section: Molecular Mechanism and Function Of Plppr3-basp1 Complex At ...mentioning

confidence: 99%

Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Kroon,

Bareesel,

Kirchner

et al. 2024

Preprint

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“…Recent evidence, however, has shown that CB1R expressed on inhibitory axons promotes inhibitory boutons, triggered by increased cAMP levels and PKA activity (Liang et al, 2021). On the other hand, the CB2R is expressed in both neurons and microglial cells, and its activation modulates neuronal excitability and neuroinflammation, respectively (den Boon et al, 2012;Komorowska-Müller & Schmöle, 2020;Stempel et al, 2016).…”

Section: Endocannabinoid Signaling In Microgliamentioning

confidence: 99%

Endocannabinoid signaling in microglia

Marinelli

Marrone

Domenico

et al. 2022

Glia

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Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an antiinflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.

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“…Further, GABA B receptor activation can impair axonal elongation (Bird and Owen, 1998;Ferguson and McFarlane, 2002;Xiang et al, 2002). Similarly, endocannabinoid CB1 receptors are highly expressed on developing corticofugal axons influencing growth cone collapse and proper targeting (Roland et al, 2014) and mediate formation and stabilization of GABAergic axonal boutons (Liang et al, 2021). Loss of CB1 receptor signaling evokes aberrant apical dendritic sprouts of migrating pyramidal neurons of the cortical plate, which impairs their migration (Díaz-Alonso et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic Silencing of Differentiating Cortical Neurons Impairs Dendritic and Axonal Growth

Gasterstädt

Schröder

Cronin

et al. 2022

Front. Cell. Neurosci.

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Electrical activity is considered a key driver for the neurochemical and morphological maturation of neurons and the formation of neuronal networks. Designer receptors exclusively activated by designer drugs (DREADDs) are tools for controlling neuronal activity at the single cell level by triggering specific G protein signaling. Our objective was to investigate if prolonged silencing of differentiating cortical neurons can influence dendritic and axonal maturation. The DREADD hM4Di couples to Gi/o signaling and evokes hyperpolarization via GIRK channels. HM4Di was biolistically transfected into neurons in organotypic slice cultures of rat visual cortex, and activated by clozapine-N-oxide (CNO) dissolved in H2O; controls expressed hM4Di, but were mock-stimulated with H2O. Neurons were analyzed after treatment for two postnatal time periods, DIV 5-10 and 10-20. We found that CNO treatment delays the maturation of apical dendrites of L2/3 pyramidal cells. Further, the number of collaterals arising from the main axon was significantly lower, as was the number of bouton terminaux along pyramidal cell and basket cell axons. The dendritic maturation of L5/6 pyramidal cells and of multipolar interneurons (basket cells and bitufted cells) was not altered by CNO treatment. Returning CNO-treated cultures to CNO-free medium for 7 days was sufficient to recover dendritic and axonal complexity. Our findings add to the view that activity is a key driver in particular of postnatal L2/3 pyramidal cell maturation. Our results further suggest that inhibitory G protein signaling may represent a factor balancing the strong driving force of neurotrophic factors, electrical activity and calcium signaling.

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Axonal CB1 Receptors Mediate Inhibitory Bouton Formation via cAMP Increase and PKA

Cited by 15 publications

References 135 publications

Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Endocannabinoid signaling in microglia

Chemogenetic Silencing of Differentiating Cortical Neurons Impairs Dendritic and Axonal Growth

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