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The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression.

ABSTRACT: GLP-1R (glucagon-like peptide-1 receptor) mediates the 'incretin effect' and many other anti-diabetic actions of its cognate ligand, GLP-1 (glucagon-like peptide-1). It belongs to the class B family of GPCRs (G protein-coupled receptors) and possesses an N-terminal putative SP (signal peptide). It has been reported that this sequence is required for the synthesis of GLP-1R and is cleaved after receptor synthesis. In the present study, we conducted an in-depth exploration towards the role of the putative SP in GLP-1R synthesis. A mutant GLP-1R without this sequence was expressed in HEK293 cells (human embryonic kidney 293 cells) and displayed normal functionality with respect to ligand binding and activation of adenylate cyclase. Thus the putative SP does not seem to be required for receptor synthesis. Immunoblotting analysis shows that the amount of GLP-1R synthesized in HEK293 cells is low when the putative SP is absent. This indicates that the role of the sequence is to promote the expression of GLP-1R. Furthermore, epitopes tagged at the N-terminal of GLP-1R are detectable by immunofluorescence and immunoblotting in our experiments. In conclusion, the present study points to different roles of SP in GLP-1R expression which broadens our understanding of the functionality of this putative SP of GLP-1R and possibly other Class B GPCRs.

SUBMITTER: Ge Y

PROVIDER: S-EPMC4240022 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression.

Ge Yunjun Y Yang Dehua D Dai Antao A Zhou Caihong C Zhu Yue Y Wang Ming-Wei MW

Bioscience reports 20141121 6

GLP-1R (glucagon-like peptide-1 receptor) mediates the 'incretin effect' and many other anti-diabetic actions of its cognate ligand, GLP-1 (glucagon-like peptide-1). It belongs to the class B family of GPCRs (G protein-coupled receptors) and possesses an N-terminal putative SP (signal peptide). It has been reported that this sequence is required for the synthesis of GLP-1R and is cleaved after receptor synthesis. In the present study, we conducted an in-depth exploration towards the role of the ...[more]

PMID: 25330813

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Project description:The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial ?-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced ?-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-?, IL-1?, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-?, IL-1?, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and ?-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated ?-endorphin expression in cultured primary microglia, whereas treatment with ?-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of ?-endorphin in vitro and in vivo and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38?, but not siRNA/p38?, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-? mRNA using siRNA fully inhibited exenatide-induced spinal microglial ?-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and ?-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated ?-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38?/CREB and subsequent IL-10 receptor/STAT3 signal pathways.SIGNIFICANCE STATEMENT Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor ?-endorphin from microglia. GLP-1 receptor agonism induces ?-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and ?-endorphin expression subsequently through the Gs-cAMP/PKA/p38?/CREB and IL-10/IL-10 receptor-?/STAT3 signal transduction pathways.

Dataset Information

The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression.

Publications

The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression.

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