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A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes.

ABSTRACT: Reelin is synthesized and secreted into extracellular matrix by cortical gamma-aminobutyric acid (GABA)ergic interneurons and binds with high affinity to the extracellular domain of integrin receptors expressed in dendritic shaft and spine postsynaptic densities (DSPSD) of pyramidal neurons. In heterozygous reeler mice, reelin bound to DSPSD, and the expression of Arc (activity-regulated cytoskeletal protein) is lower than in wild-type mice. We studied the effect of reelin on Arc and total protein synthesis in synaptoneurosomes (SNSs) prepared from mouse neocortex. Recombinant full-length mouse reelin displaces the high affinity (K(D) = 60 fM) binding of [(125)I]echistatin (a competitive integrin receptor antagonist) to integrin receptors with a K(i) of 22 pM and with a Hill slope close to 1. Echistatin (50-100 nM) competitively antagonizes and abates reelin binding. The addition of reelin (2-40 pM) to SNSs enhances the incorporation of [(35)S]methionine into Arc and other rapidly translated proteins in a concentration-dependent manner. This incorporation is virtually abolished by 50-100 nM echistatin or by 5-10 nM rapamycin, a blocker of the mammalian target of rapamycin kinase. We conclude that reelin binds with high affinity to integrin receptors expressed in SNSs and thereby activates Arc protein synthesis.

SUBMITTER: Dong E

PROVIDER: S-EPMC154370 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes.

Dong Erbo E Caruncho Hector H Liu Wen Sheng WS Smalheiser Neil R NR Grayson Dennis R DR Costa Erminio E Guidotti Alessandro A

Proceedings of the National Academy of Sciences of the United States of America 20030421 9

Reelin is synthesized and secreted into extracellular matrix by cortical gamma-aminobutyric acid (GABA)ergic interneurons and binds with high affinity to the extracellular domain of integrin receptors expressed in dendritic shaft and spine postsynaptic densities (DSPSD) of pyramidal neurons. In heterozygous reeler mice, reelin bound to DSPSD, and the expression of Arc (activity-regulated cytoskeletal protein) is lower than in wild-type mice. We studied the effect of reelin on Arc and total prote ...[more]

PMID: 12707415

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Project description:BackgroundReelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown.Methodology/principal findingsCombining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR). We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs) to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons.Conclusions/significanceOur data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia.

Dataset Information

A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes.

Publications

A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes.

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