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Role of the signal peptide in the synthesis and processing of the glucagon-like peptide-1 receptor

By Y. Huang, Graeme F. Wilkinson and Gary B. Willars


This paper was published as British Journal of Pharmacology, 2010, 159 (1), pp. 237-251. It is available from Doi: 10.1111/j.1476-5381.2009.00517.xMetadata only entryBackground and purpose: The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B of the G protein-coupled receptor superfamily and is a target for treatment of type 2 diabetes. Family B G protein-coupled receptors contain a putative N-terminal signal peptide, but its role in receptor synthesis and trafficking are unclear. Further, the signal peptide is not cleaved in at least one family member.\ud \ud Experimental approach: We examined receptor glycosylation and the role of the signal peptide in GLP-1R synthesis and trafficking using constructs containing epitope tags at the N- and/or C-terminus and in which the signal peptide sequence was either present or absent.\ud \ud Key results: The signal peptide was absolutely required for GLP-1R synthesis but could be substituted to some extent by increasing positive charge in the N-terminal region of the receptor flanking the signal peptide. The signal peptide is cleaved during synthesis and processing of the receptor. An enhanced GFP-epitope tag at the N-terminus of the receptor permitted synthesis of the receptor but blocked signal peptide cleavage and prevented trafficking to the plasma membrane. Cleavage site mutation allowed synthesis of a full-length receptor, blocked signal peptide cleavage and caused retention within the endoplasmic reticulum.\ud \ud Conclusions and implications: Signal peptide cleavage was not essential for receptor synthesis but was obligatory for processing and trafficking of receptors to the plasma membrane. Further, the GLP-1R is subject to N-linked glycosylation and only the mature, fully glycosylated form of the receptor is present in the plasma membrane. Inhibition of glycosylation prevents processing and cell surface expression of the GLP-1R

Publisher: Wiley-Blackwell on behalf of the British Pharmacological Society.
Year: 2010
DOI identifier: 10.1111/j.1476-5381.2009.00517.x
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