Presynaptic Type III Neuregulin1-ErbB signaling targets α7 nicotinic acetylcholine receptors to axons

Integrated Program in Cellular, Molecular and Biophysical Studies, Columbia University, New York, NY 10032, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 06/2008; 181(3):511-21. DOI: 10.1083/jcb.200710037
Source: PubMed

ABSTRACT Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

Download full-text


Available from: David A Talmage, Aug 18, 2015
  • Source
    • "Similarly, postnatal ablation of NR1 in cortical and hippocampal GABAergic neurons leads to schizophrenia-related symptoms after adolescence, whereas a conditional NR1 knockout in which NMDAR deletion occurring after adolescence does not result in such abnormalities (Belforte et al., 2010). Loss or reduction of α7 nAChRs may lead to such profound glutamatergic hypofunction in PV-positive interneurons through neuregulin 1, NRG1/ErbB4 pathways in schizophrenia, since both α7 nAChRs and NRG1 are schizophrenia risk genes that associate with NMDARs and excitatory synapse formation on PV-positive interneurons (Hahn et al., 2006; Hancock et al., 2008; Ting et al., 2011). Our findings thus implicate NMDAR hypofunction in GABAergic interneurons, which may contribute to cortical dysfunction leading to impaired attention, working-memory and learning in α7 nAChR deletion models. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dysfunction of cortical parvalbumin (PV)-containing GABAergic interneurons has been implicated in cognitive deficits of schizophrenia. In humans microdeletion of the CHRNA7 (α7 nicotinic acetylcholine receptor, nAChR) gene is associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia while in mice similar deletion causes analogous abnormalities including impaired attention, working-memory and learning. However, the pathophysiological roles of α7 nAChRs in cortical PV GABAergic development remain largely uncharacterized. In both in vivo and in vitro models, we identify here that deletion of the α7 nAChR gene in mice impairs cortical PV GABAergic development and recapitulates many of the characteristic neurochemical deficits in PV-positive GABAergic interneurons found in schizophrenia. α7 nAChR null mice had decreased cortical levels of GABAergic markers including PV, Glutamic Acid Decarboxylase 65/67 (GAD65/67) and the α1 subunit of GABAA receptors, particularly reductions of PV and GAD67 levels in cortical PV-positive interneurons during late postnatal life and adulthood. Cortical GABAergic synaptic deficits were identified in the prefrontal cortex of α7 nAChR null mice and α7 nAChR null cortical cultures. Similar disruptions in development of PV-positive GABAergic interneurons and perisomatic synapses were found in cortical cultures lacking α7 nAChRs. Moreover, NMDA receptor expression was reduced in GABAergic interneurons, implicating NMDA receptor hypofunction in GABAergic deficits in α7 nAChR null mice. Our findings thus demonstrate impaired cortical PV GABAergic development and multiple characteristic neurochemical deficits reminiscent of schizophrenia in cortical PV-positive interneurons in α7 nAChR gene deletion models. This implicates crucial roles of α7 nAChRs in cortical PV GABAergic development and dysfunction in schizophrenia and other neuropsychiatric disorders.
    Molecular and Cellular Neuroscience 06/2014; 61. DOI:10.1016/j.mcn.2014.06.007 · 3.73 Impact Factor
  • Source
    • "Type III Nrg1 is distinct from the other two types of Nrg1 and contains an extra N-terminal transmembrane structure. In type III Nrg1, initial proteolysis frees the EGF-like domain from the membrane and leads to juxtacrine signaling characterized by reciprocal intercellular communication (Bao et al. 2003; Hancock et al. 2008). Further cleavage releases a shorter peptide containing the EGF-like domain that functions in autocrine/paracrine interactions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The binding of Neuregulin-1 (Nrg1) to the epidermal growth factor family of receptor tyrosine kinases (ErbB) mediates intercellular and intracellular communication and regulates a broad spectrum of biological processes, such as tumorigenesis and myelination. Recombinant Nrg1 has been shown to control prolactin (PRL) secretion from rat prolactinoma GH3 cells. However, the endogenous expression of Nrg1 and its role in PRL secretion in GH3 cells are not known. In this study, we demonstrate that type III Nrg1 isoforms are endogenously expressed in GH3 cells. An in vitro functional analysis by using short interfering RNA against Nrg1 has revealed that endogenous Nrg1 regulates PRL secretion from GH3 cells in part in an ErbB-3-receptor-dependent manner, with no significant effects on growth hormone secretion. Therefore, Nrg1 is a specific modulator of PRL secretion in GH3 cells. Additionally, the co-localization of Nrg1 and ErbB-2 receptor, which is shared by both ErbB-3 and ErbB-4 receptors in the formation of heterodimers, has been detected in one out of five human prolactinoma tissues. Our findings suggest that GH3 cells intrinsically express a group of type III Nrg1 isoforms that regulate PRL secretion through an autocrine/paracrine mechanism. Further investigation into the role of Nrg1 on PRL secretion should provide clues to advance the clinical management of prolactinoma.
    Cell and Tissue Research 03/2011; 344(2):313-20. DOI:10.1007/s00441-011-1157-y · 3.33 Impact Factor
  • Source
    • "It has been shown that chronic nicotine-induced up-regulation of a7 nAChRs, but not high-affinity nAChRs, requires protein synthesis and glycosylation in vitro (Kawai and Berg 2001). However, rapid protein synthesis independent up-regulation of a7 nAChRs due to translocation of intracellular pools of a7 nAChRs has been shown in dorsal root ganglions and in Xenopus oocytes (Cho et al. 2005; Hancock et al. 2008), suggesting different mechanisms for acute and prolonged upregulation of a7 nAChRs. As repeated administration is more relevant in a clinical perspective, we proceeded to investigate the effects of repeated (7 days) administration of A-582941, and showed that this leads to a significantly increased [ 125 I]-BTX binding, not only in the prefrontal regions as seen with acute treatment, but also in the parietal cortex and hippocampus . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target. Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 nAChR positive allosteric modulators PNU-120596 and NS1738 do not increase [(125)I]-BTX binding. Furthermore, A-582941-induced increase in Arc and c-fos mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the alpha7 nAChRs remain responsive. Contrarily, A-582941-induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of alpha7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling pathways. Additionally, our data suggest a fundamental difference between the sequelae of repeated administration with agonists and allosteric modulators of the alpha7 nAChR.
    Journal of Neurochemistry 08/2010; 114(4):1205-16. DOI:10.1111/j.1471-4159.2010.06845.x · 4.24 Impact Factor
Show more