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Expression of Neurexin, Neuroligin, and Their Cytoplasmic Binding Partners in the Pancreatic beta-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: 4.64). 09/2008; 149(12):6006-17. DOI: 10.1210/en.2008-0274
Source: PubMed

ABSTRACT 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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    • "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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    • "The current data suggest that Neurexin–Neuroligin binding is governed by a complex code that is based on the type of isoforms and splice variants involved, calcium binding, and glycosylation (Sudhof, 2008). Neuroligin 1 expression is mainly restricted to the CNS, while Neuroligins 2–4 present a broader expression pattern (Song et al., 1999; Philibert et al., 2000; Bolliger et al., 2001; Gilbert et al., 2001; Kang et al., 2004; Suckow et al., 2008). Some lines of evidence suggest that the expression of Neuroligins may differ between species. "
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    ABSTRACT: β cells express many protein constituents of the neurotransmitter exocytotic machinery, including a family of synaptic adhesion molecules called neurexins (NRXNs) (1). α-NRXNs help couple Ca2+ channels to the exocytotic machinery in neurons and pituitary cells (2). We hypothesized that α-NRXNs play a comparable role in β cells, participating in Ca2+-dependent exocytosis of insulin- containing secretory granules. Using absolute RT-qPCR, we determined that in rat β-cells, NRXN1α and 2β were the most abundant isoforms of NRXN and transcript levels were comparable to rat brain. Overexpression of NRXN1α in INS- 1E cells resulted in an increase in glucose-stimulated insulin secretion (GSIS). Exocytotic proteins and known neuronal NRXN binding partners CASK and Munc18 co-immunoprecipitated with NRXN1 from INS-1E cells. siRNA knockdown of NRXN1 in INS-1E cells resulted in an increase in insulin secretion at basal and high glucose concentrations. This was accompanied by increases in cellular insulin content and gene expression. Under glucotoxic conditions, NRXN expression in INS-1 cells was decreased. We conclude that NRXNs are involved in the exocytosis of insulin-containing secretory granules from β cells, likely in a manner similar to that of synaptic vesicle exocytosis in neurons.
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