Expression of Neurexin, Neuroligin, and Their Cytoplasmic Binding Partners in the Pancreatic β-Cells and the Involvement of Neuroligin in Insulin Secretion

Department of Medicine, Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093, USA.
Endocrinology (Impact Factor: 4.5). 09/2008; 149(12):6006-17. DOI: 10.1210/en.2008-0274
Source: PubMed


The composition of the beta-cell exocytic machinery is very similar to that of neuronal synapses, and the developmental pathway of beta-cells and neurons substantially overlap. beta-Cells secrete gamma-aminobutyric acid and express proteins that, in the brain, are specific markers of inhibitory synapses. Recently, neuronal coculture experiments have identified three families of synaptic cell-surface molecules (neurexins, neuroligins, and SynCAM) that drive synapse formation in vitro and that control the differentiation of nascent synapses into either excitatory or inhibitory fully mature nerve terminals. The inhibitory synapse-like character of the beta-cells led us to hypothesize that members of these families of synapse-inducing adhesion molecules would be expressed in beta-cells and that the pattern of expression would resemble that associated with neuronal inhibitory synaptogenesis. Here, we describe beta-cell expression of the neuroligins, neurexins, and SynCAM, and show that neuroligin expression affects insulin secretion in INS-1 beta-cells and rat islet cells. Our findings demonstrate that neuroligins and neurexins are expressed outside the central nervous system and help confer an inhibitory synaptic-like phenotype onto the beta-cell surface. Analogous to their role in synaptic neurotransmission, neurexin-neuroligin interactions may play a role in the formation of the submembrane insulin secretory apparatus.

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Available from: Steven D Chessler, Feb 18, 2015
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    • "Interestingly in a recent study a family was reported in which a heterozygous deletion comprising the upstream promoter and first intron of NRXN1 was seen in a patient with diabetes mellitus (Duong et al., 2012). In addition, it is of note that the neurexins are expressed in the β-cells of the pancreas, therefore any aberrations in the protein could potentially lead to a decrease in function of the pancreas (Suckow et al., 2008). Together with our observations , these data warrant further investigation of the involvement of NRXN1 in diabetes. "
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    ABSTRACT: We report a consanguineous Pakistani family with a severe congenital microcephaly syndrome resembling Seckel syndrome and Jawad syndrome. The affected individuals in this family were born to consanguineous parents of whom the mother presented with mild intellectual disability (ID), epilepsy and diabetes mellitus. The two living affected brothers presented with microcephaly, white matter disease of the brain, hyponychia, dysmorphic facial features with synophrys, epilepsy, diabetes mellitus and ID. Genotyping with a 250K SNP array in both affected brothers revealed an 18MB homozygous region on chromosome 18p11.21q12.1 encompassing the SCKL2 locus of Seckel and Jawad syndrome. Sequencing of the RBBP8, underlying Seckel and Jawad syndrome, identified the novel mutation c.919A>G, p.Arg307Gly, segregating in a recessive manner in the family. In addition, in the two affected brothers and their mother we have also found a heterozygous 607kb deletion, encompassing exons 13-19 of NRXN1. Bidirectional sequencing of the coding exons of NRXN1 did not reveal any other mutation on the other allele. It thus appears that the phenotype of the mildly affected mother can be explained by the NRXN1 deletion, whereas the more severe and complex microcephalic phenotype of the two affected brothers is due to the simultaneous deletion in NRXN1 and the homozygous missense mutation affecting RBBP8.
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    • "In the CNS, coculture experiments using nonneuronal cell lines expressing members of the neuroligins gene families revealed that neuroligins specifically induce presynaptic differentiation and also help to drive the functional of synapses [27], which is the foundation of information transmission among neurons by transporting neurotransmitter. A number of studies have shown that the vertebrate neuroligin-neurexin complex appears to influence synapse specificity through excitatory versus inhibitory synapse development, and thus is predicted to influence the excitatory/inhibitory synapse ratio in the brain[28]–[31]. "
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    ABSTRACT: The aim of this study was to investigate the expression and significance of neuroligins in myenteric cells of Cajal (ICC-MY) in Hirschsprung's disease (HSCR). Longitudinal muscle with adherent myenteric plexus (LMMP) from surgical excision waste colon of HSCR children were prepared by peeling off the mucous layer, sub-mucosal layer and circular muscle. Neuroligins, c-Kit (c-Kit-immunoreactivity representing ICC) and their relationship were assessed by double labeling immunofluorescence staining. ICC-MY were dissociated and cultured from LMMP by enzymolysis method, and were purified and analyzed using a combination of magnetic-activated cell sorting (MACS) and flow cytometry (FCM). Western-blot analysis was applied to compare and evaluate the expression levels of neuroligins in ICC-MY which were dissociated from different segments of HSCR (ganglionic colonic segment, transitional colonic segment and aganglionic colonic segment). Neuroligins and c-Kit were expressed on the same cells (ICC-MY); ICC-MY were dissociated, cultured and purified. For HSCR, neuroligins were expressed significantly in ICC-MY from ganglionic colonic segments, moderately in those from transitional colonic segments and down-regulated significantly in those from aganglionic colonic segments. Neuroligins were expressed in ICC-MY of human beings, and the expression varies from different segments of HSCR. This abnormal expression might play an important role in the pathogenesis of this disease through affecting the synaptic function of ICC-MY.
    Preview · Article · Jun 2013 · PLoS ONE
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    • "Neuroligin-2 is the predominant neuroligin isoform in islets and insulinoma cells [13]. Neuroligin-1 transcripts are also present in islet tissue [13]. "
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    ABSTRACT: Neuroligin-2 is a transmembrane, cell-surface protein originally identified as an inhibitory synapse-associated protein in the central nervous system. Neuroligin-2 is also present on the pancreatic beta-cell surface, and there it engages in transcellular interactions that drive functional maturation of the insulin secretory machinery; these are necessary for normal insulin secretion. The effects of neuroligin-2 deficiency on brain and neuronal function and morphology and on behavior and coordination have been extensively characterized using neuroligin-2 knockout mice. The effects of absent neuroligin-2 expression on islet development and function, however, are unknown. Here, to help test whether neuroligin-2 is necessary for normal islet development, we characterized islet morphology in mice lacking neuroligin-2. To test whether-as predicted by our earlier co-culture studies-absence of neuroligin-2 impairs beta cell function, we compared glucose-stimulated insulin secretion by islets from mutant and wild-type mice. Our results show that while islets from neuroligin-2-deficient mice do not to appear to differ architecturally from wild-type islets, they are smaller, fewer in number, and contain beta cells with lower insulin content. Evaluation of transcript levels suggests that upregulation of neuroligin-1 helps compensate for loss of neuroligin-2. Surprisingly, under both basal and stimulating glucose levels, isolated islets from the knockout mice secreted more of their intracellular insulin content. Rat islets with shRNA-mediated neuroligin-2 knockdown also exhibited increased insulin secretion. Neurexin transcript levels were lower in the knockout mice and, consistent with our prior finding that neurexin is a key constituent of the insulin granule docking machinery, insulin granule docking was reduced. These results indicate that neuroligin-2 is not necessary for the formation of pancreatic islets but that neuroligin-2 influences islet size and number. Neuroligin-2-perhaps through its effects on the expression and/or activity of its binding partner neurexin-promotes insulin granule docking, a known constraint on insulin secretion.
    Full-text · Article · Jun 2013 · PLoS ONE
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