Premium Role of the signal peptide in the synthesis and processing of the glucagon‐like peptide‐1 receptorPremium
british journal of pharmacology
Background 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. 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. 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. 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.
Subject(s)5 ht5a receptor , agonist , biochemistry , biology , chemistry , g protein coupled receptor , gene , glucagon like peptide 1 receptor , microbiology and biotechnology , peptide , peptide sequence , receptor , signal peptidase , signal peptide
SCImago Journal Rank2.432
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