Protein processing and releases of neuregulin‐1 are regulated in an activity‐dependent manner

Ozaki, Miwako; Itoh, Kouich; Miyakawa, Yukie; Kishida, Haruo; Hashikawa, Tsutomu

doi:10.1111/j.1471-4159.2004.02719.x

Cited by 79 publications

(69 citation statements)

References 51 publications

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“…Fine, dissected, rat brain was performed with the aid of markers and ascertained by other means (Ozaki et al 2004). One or two microgram of total RNA was subjected to direct cDNA synthesis using Superscript II RNaseH minus reverse transcriptase with the AP primer (an oligo-dT primer with an attached sequence) under the conditions recommended for the 3¢-RACE system (Invitrogen, UK).…”

Section: Rt-pcrmentioning

confidence: 99%

Frequent occurrence of protein isoforms with or without a single amino acid residue by subtle alternative splicing: the case of Gln in DRPLA affects subcellular localization of the products

et al. 2005

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Protein isoforms with or without a single amino acid residue make a subtle difference. It has been documented on a few genes that alternative splicing generated such isoforms; however, the fact has attracted little attention. We became aware of a subtle sequence difference in DRPLA, a polyglutamine disease gene for dentatorubral pallidoluysian atrophy. Some reported cDNA sequences lacked 3 nucleotides (nt) (CAG), which were positioned apart from the expandable and polymorphic CAG repeats and also coded for glutamine. We experimentally confirmed that the difference was indeed generated by alternative splicing utilizing two acceptors separated by 3 nt. In DRPLA, the expression ratio of two mRNA isoforms was almost constant among tissues, with the CAG-included form being major. The glutamine-included protein isoform was more predominantly localized in the nucleus. Database searching revealed that alternative splice acceptors, as well as donors, are frequently situated very close to each other. We experimentally confirmed two mRNA isoforms of 3 nt difference in more than 200 cases by RT-PCR and found interesting features associated with this phenomena. Inclusion of 3 nt tends to result in single amino acid inclusion despite the phase of translational frame. The expression ratio sometimes varied extensively among tissues.

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Section: Rt-pcrmentioning

confidence: 99%

Frequent occurrence of protein isoforms with or without a single amino acid residue by subtle alternative splicing: the case of Gln in DRPLA affects subcellular localization of the products

et al. 2005

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“…Proteolytic inhibitory profiling suggests that Nrg1 can also be processed by a metalloprotease (12,15,16). In this study, we investigated the potential role of ADAM10 (a disintegrin and metalloproteinase 10) and ADAM17 in cleaving Nrg1.…”

Section: Members Of the Neuregulin (Nrg)mentioning

confidence: 99%

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Luo

Prior

et al. 2011

Journal of Biological Chemistry

107

117

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Neuregulin-1 (Nrg1) is encoded by a single gene and exists in naturally secreted and transmembrane isoforms. Nrg1 exerts its signaling activity through interaction with its cognate ErbB receptors. Multiple membrane-anchored Nrg1 isoforms, present in six different membrane topologies, must be processed by a protease to initiate a signaling cascade. Here, we demonstrate that BACE1 and ADAM10 can process type I and III Nrg1 at two adjacent sites. Our cleavage site mapping experiments showed that the BACE1 cleavage site is located eight amino acids downstream of the ADAM10 cleavage site, and this order of cleavage is the opposite of amyloid precursor protein cleavage by these two enzymes. Cleavages were further confirmed via optimized electrophoresis. Cleavage of type I or III Nrg1 by ADAM10 and BACE1 released a signaling-capable N-terminal fragment (ntf), either Nrg1-ntf␣ or Nrg1-ntf␤, which could similarly activate an ErbB receptor as evidenced by increased phosphorylation of Akt and ERK, two downstream signaling molecules. Although both Nrg1-ntf␣ and Nrg1-ntf␤ could initiate a common signaling cascade, inhibition or down-regulation of ADAM10 alone in a co-culture system did not affect normal myelination, whereas specific inhibition of BACE1 impaired normal myelination. Thus, processing of Nrg1 by BACE1 appears to be more critical for regulating myelination. Our results imply that a significant inhibition of BACE1 could potentially impair Nrg1 signaling activity in vivo. Members of the neuregulin (Nrg)3 family of proteins contain an EGF-like domain that mediates cell-cell signaling functions via interaction with cognate ErbB receptors (1, 2). The Nrg protein family consists of four members (Nrg1-Nrg4), with Nrg1 being the most well characterized. Because of multiple splicing events, mammalian Nrg1 has a total of 33 isoforms that can be distinguished by six different membrane topologies (types I-VI) (3). Mice with a genetic deletion of Nrg1 are embryonic-lethal due to circulatory failure and defects in neural and cardiac development (4), indicating the importance of Nrg1 in normal growth. As a critical signaling molecule, Nrg1 has also been linked to developmental abnormalities and pathogenesis of multiple diseases. For example, Nrg1 polymorphism has been identified as a risk factor for schizophrenia (5).Mouse genetic studies also demonstrate that type III Nrg1 is a master regulator of myelination; its level in axons is correlated with the thickness of the myelin sheath (6, 7).Most of the 33 Nrg1 isoforms are membrane-anchored ligands, and proteolytic cleavage of these membrane-bound Nrg1 isoforms is required for the secreted Nrg1 fragment to bind to its cognate receptor, an ErbB2/ErbB3 heterodimer or ErbB4 homodimer (8 -10). In our recent study of Alzheimer ␤-secretase (BACE1), we demonstrated that membrane-anchored type I and III ␤1 Nrg1 isoforms are cleaved by BACE1 at the site between residues EF and ME, ϳ10 residues away from the transmembrane region (11). In BACE1-null mice, the cleavage of type I and III ␤1 ...

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“…Although multiple isoforms of NRG1 precursor proteins (types I-VI) are generated by alternative splicing, all NRG1 isoforms contain an epidermal growth factor (EGF)-like core domain (eNRG1) (Burden and Yarden, 1997;Buonanno and Fischbach, 2001;Mei and Xiong, 2008). Soluble forms of NRG1 isoforms are produced from membrane-anchored precursors by metalloproteases: these variants are liberated in a neural activitydependent manner to bind ErbB3 or ErbB4 NRG1 receptors (Falls, 2003;Ozaki et al, 2004;Li et al, 2007). Stimulation of ErbB4 on neuronal cell surfaces or postsynaptic membranes alters the expression of NMDA and GABA A receptors (Ozaki et al, 1997;Okada and Corfas, 2004;Xie et al, 2004) and affects clustering of ␣7 nicotinic acetylcholine receptors (Zhong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

Abe¹,

Namba²,

Kato³

et al. 2011

J. Neurosci.

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Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes.

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Protein processing and releases of neuregulin‐1 are regulated in an activity‐dependent manner

Cited by 79 publications

References 51 publications

Frequent occurrence of protein isoforms with or without a single amino acid residue by subtle alternative splicing: the case of Gln in DRPLA affects subcellular localization of the products

Frequent occurrence of protein isoforms with or without a single amino acid residue by subtle alternative splicing: the case of Gln in DRPLA affects subcellular localization of the products

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

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