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Reelin signaling modulates GABA_B receptor function in the neocortex.

ABSTRACT: Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post-natal cortical network function, which is poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock-out (Reln^cKO ) mouse, and induced Reelin deficiency post-natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Blocking Reelin binding to its receptors ApoER2 and VLDLR resulted in a similar effect. Hyperexcitability in Reln^cKO organotypic slice cultures could be rescued by co-culture with wild-type organotypic slice cultures. Moreover, the GABA_B receptor (GABA_B R) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABA_B Rs in Reln^cKO mice. Immunolabeling of Reln^cKO cortical slices revealed a reduction in GABA_B R1 and GABA_B R2 surface expression at the plasma membrane and western blot of Reln^cKO cortical tissue revealed decreased phosphorylation of the GABA_B R2 subunit at serine 892 and increased phosphorylation at serine 783, reflecting receptor deactivation and proteolysis. These data show a role of Reelin in controlling early network activity, by modulating GABA_B R function. Cover Image for this issue: https://doi.org/10.1111/jnc.15054.

SUBMITTER: Hamad MIK

PROVIDER: S-EPMC7442713 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Reelin signaling modulates GABA<sub>B</sub> receptor function in the neocortex.

Hamad Mohammad I K MIK Jbara Abdalrahim A Rabaya Obada O Petrova Petya P Daoud Solieman S Melliti Nesrine N Meseke Maurice M Lutz David D Petrasch-Parwez Elisabeth E Schwitalla Jan Claudius JC Mark Melanie D MD Herlitze Stefan S Reiss Gebhard G Herz Joachim J Förster Eckart E

Journal of neurochemistry 20200313 5

Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post-natal cortical network function, which is poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock-out (Reln<sup>cKO</sup> ) mouse, and induced Reelin deficiency post-natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Bl ...[more]

PMID: 32083308

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Project description:We report the modification of MIDD0301, an imidazodiazepine GABAA receptor (GABAAR) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABAAR binding site of clonazepam, with IC50 values of 576 and 242 nM, respectively. Molecular docking analysis, using the available α1β3γ2 GABAAR structural data, suggests binding of the diazepine core between the α1+/γ2- interface, whereas alkyl substituents are located outside the binding site and thus interact with the protein surface and solvent molecules. The physicochemical properties of these compounds are very different. The solubility of PI310 is low in water. PEGylation of PI320 significantly improves aqueous solubility and cell permeability. Neither compound is toxic in HEK293 cells following exposure at >300 μM for 18 h. Ex vivo studies using guinea pig tracheal rings showed that PI310 was unable to relax the constricted airway smooth muscle. In contrast, PI320 induced muscle relaxation at organ bath concentrations as low as 5 μM, with rapid onset (15 min) at 25 μM. PI320 also reduced airway hyper-responsiveness in vivo in a mouse model of steroid-resistant lung inflammation induced by intratracheal challenge with INFγ and lipopolysaccharide (LPS). At nebulized doses of 7.2 mg/kg, PI320 and albuterol were equally effective in reducing airway hyper-responsiveness. Ten minutes after nebulization, the lung concentration of PI320 was 50-fold that of PI310, indicating superior availability of PI320 when nebulized as an aqueous solution. Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/pharmacodynamic properties of PI320 when administered orally.

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Reelin signaling modulates GABA_B receptor function in the neocortex.

Publications

Reelin signaling modulates GABA<sub>B</sub> receptor function in the neocortex.

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Dataset Information

Reelin signaling modulates GABAB receptor function in the neocortex.

Publications

Reelin signaling modulates GABA<sub>B</sub> receptor function in the neocortex.

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OmicsDI is part of the ELIXIR infrastructure

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Reelin signaling modulates GABA_B receptor function in the neocortex.