The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Fumagalli, Armando; Heuninck, Joyce; Pizzoccaro, Anne; Moutin, Enora; Koenen, Joyce; Séveno, Martial; Durroux, Thierry; Junier, Marie Pierre; Schlecht-Louf, Géraldine; Bachelerie, Françoise; Schütz, Dagmar; Stumm, Ralf; Smit, Martine J.; Guérineau, Nathalie C.; Chaumont‐Dubel, Séverine; Marin, Philippe

doi:10.1038/s41467-020-18634-y

Cited by 31 publications

(39 citation statements)

References 71 publications

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“…Here, we confirm their data, and furthermore demonstrate that those GRKs are also involved in the recruitment mechanism of β-arrestin1 and β-arrestin2. To finetune insight into phospho-barcoding within the ACKR3 C-terminus, involvement of other common GPCR kinases (PKA, PKC) and kinases identified in pulldown experiments of ACKR3 should be investigated as well [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Yet, the molecular mechanisms by which ACKR3 contributes to these processes is unclear. Since it does not seem to signal directly via G proteins in most cell types, with the exception of astrocytes [ 13 ], the receptor acts as a β-arrestin biased GPCR [ 14 ]. For classical GPCRs, β-arrestins act as adaptor proteins, facilitating desensitization via internalization into clathrin-coated pits [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Zarca

Pérez

Bor

et al. 2021

Cells

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Background: The atypical chemokine receptor 3 (ACKR3) belongs to the superfamily of G protein-coupled receptors (GPCRs). Unlike classical GPCRs, this receptor does not activate G proteins in most cell types but recruits β-arrestins upon activation. ACKR3 plays an important role in cancer and vascular diseases. As recruitment of β-arrestins is triggered by phosphorylation of the C-terminal tail of GPCRs, we studied the role of different potential phosphorylation sites within the ACKR3 C-tail to further delineate the molecular mechanism of internalization and trafficking of this GPCR. Methods: We used various bioluminescence and fluorescence resonance energy transfer-based sensors and techniques in Human Embryonic Kidney (HEK) 293T cells expressing WT or phosphorylation site mutants of ACKR3 to measure CXCL12-induced recruitment of β-arrestins and G-protein-coupled receptor kinases (GRKs), receptor internalization and trafficking. Results: Upon CXCL12 stimulation, ACKR3 recruits both β-arrestin 1 and 2 with equivalent kinetic profiles. We identified interactions with GRK2, 3 and 5, with GRK2 and 3 being important for β-arrestin recruitment. Upon activation, ACKR3 internalizes and recycles back to the cell membrane. We demonstrate that β-arrestin recruitment to the receptor is mainly determined by a single cluster of phosphorylated residues on the C-tail of ACKR3, and that residue T352 and in part S355 are important residues for β-arrestin1 recruitment. Phosphorylation of the C-tail appears essential for ligand-induced internalization and important for differential β-arrestin recruitment. GRK2 and 3 play a key role in receptor internalization. Moreover, ACKR3 can still internalize when β-arrestin recruitment is impaired or in the absence of β-arrestins, using alternative internalization pathways. Our data indicate that distinct residues within the C-tail of ACKR3 differentially regulate CXCL12-induced β-arrestin recruitment, ACKR3 trafficking and internalization.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Zarca

Pérez

Bor

et al. 2021

Cells

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“…To this end, we seek unique EL1 and/or EL2 patterns of Cx GJC by selecting the homomeric Cx43 GJC as prototype. Cx43 GJCs are widespread in the brain, connecting the brain-specific astrocytic cells [ 19 , 20 ]. Also, Cx43 GJCs are bound with a variety of tissue cell contacts outside the brain, including heart [ 21 ] and kidney [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

et al. 2021

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Connexin (Cx) proteins establish intercellular gap junction channels (Cx GJCs) through coupling of two apposed hexameric Cx hemichannels (Cx HCs, connexons). Pre- and post-GJ interfaces consist of extracellular EL1 and EL2 loops, each with three conserved cysteines. Previously, we reported that known peptide inhibitors, mimicking a variety of Cx43 sequences, appear non-selective when binding to homomeric Cx43 vs. Cx36 GJC homology model subtypes. In pursuit of finding potentially Cx subtype-specific inhibitors of connexon-connexon coupling, we aimed at to understand better how the GJ interface is formed. Here we report on the discovery of Cx GJC subtype-specific protein stabilization centers (SCs) featuring GJ interface architecture. First, the Cx43 GJC homology model, embedded in two opposed membrane bilayers, has been devised. Next, we endorsed the fluctuation dynamics of SCs of the interface domain of Cx43 GJC by applying standard molecular dynamics under open and closed cystine disulfide bond (CS-SC) preconditions. The simulations confirmed the major role of of the unique trans-GJ SC pattern comprising conserved (55N, 56T) and non-conserved (57Q) residues of the apposed EL1 loops in the stabilization of the GJC complex. Importantly, clusters of SC patterns residing close to the GJ interface domain appear to orient the interface formation via the numerous SCs between EL1 and EL2. These include central 54CS-S198C or 61CS-S192C contacts with residues 53R, 54C, 55N, 197D, 199F or 64V, 191P, respectively. In addition, we revealed that GJC interface formation is favoured when the psi dihedral angle of the nearby 193P residue is stable around 180° and the interface SCs disappear when this angle moves to the 0° to −45° range. The potential of the association of non-conserved residues with SC motifs in connexon-connexon coupling makes the development of Cx subtype-specific inhibitors viable.

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“…However, this issue warrants further clarification. Additionally, it was recently demonstrated that following CXCL12 treatment, ACKR3 impairs astrocytic gap-junctional communication by inducing a Cx43 internalization in a β-arrestin2-dependent manner [ 29 ], whereas CXCR4 leads to NF-Kβ activation with consequent tumor necrosis factor α (TNFα) and glutamate release from these cells [ 30 – 32 ]. Therefore, these findings suggest that CXCR4 and CXCR7 may serve distinct functions via different signaling pathways in astrocytes.…”

Section: Chemokine Action From Synapses To Behaviormentioning

confidence: 99%

“…Moreover, gap junction networks were demonstrated to play an essential role in complex brain functions, including cognition and behavior (for a review: [ 50 ]). As ACKR3 was demonstrated to induce the internalization of Cx43 [ 29 ], future studies aimed at establishing its functional significance and whether other chemokine receptors may elicit similar actions are warranted.…”

Section: Chemokine Action From Synapses To Behaviormentioning

confidence: 99%

Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior

Sowa

Tokarski

2021

Pharmacol. Rep

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Accumulating evidence highlights chemokines as key mediators of the bidirectional crosstalk between neurons and glial cells aimed at preserving brain functioning. The multifaceted role of these immune proteins in the CNS is mirrored by the complexity of the mechanisms underlying its biological function, including biased signaling. Neurons, only in concert with glial cells, are essential players in the modulation of brain homeostatic functions. Yet, attempts to dissect these complex multilevel mechanisms underlying coordination are still lacking. Therefore, the purpose of this review is to summarize the current knowledge about mechanisms underlying chemokine regulation of neuron–glia crosstalk linking molecular, cellular, network, and behavioral levels. Following a brief description of molecular mechanisms by which chemokines interact with their receptors and then summarizing cellular patterns of chemokine expression in the CNS, we next delve into the sequence and mechanisms of chemokine-regulated neuron–glia communication in the context of neuroprotection. We then define the interactions with other neurotransmitters, neuromodulators, and gliotransmitters. Finally, we describe their fine-tuning on the network level and the behavioral relevance of their modulation. We believe that a better understanding of the sequence and nature of events that drive neuro-glial communication holds promise for the development of new treatment strategies that could, in a context- and time-dependent manner, modulate the action of specific chemokines to promote brain repair and reduce the neurological impairment.

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The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Cited by 31 publications

References 71 publications

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior

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