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Specific ligands as pharmacological chaperones: The transport of misfolded G‐protein coupled receptors to the cell surface
Author(s) -
Nakamura Motonao,
Yasuda Daisuke,
Hirota Nobuaki,
Shimizu Takao
Publication year - 2010
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.344
Subject(s) - g protein coupled receptor , endoplasmic reticulum , chaperone (clinical) , microbiology and biotechnology , receptor , protein folding , transmembrane protein , membrane protein , transmembrane domain , transport protein , cell surface receptor , biology , cell membrane , er retention , intracellular , cell , chemistry , biochemistry , signal transduction , membrane , gene , pathology , medicine , mutant
In the endoplasmic reticulum (ER), quality control mechanisms distinguish between correctly and incorrectly folded structures to ensure that aberrant proteins are not processed along the secretory pathway. Numerous studies have demonstrated the functional rescue of ER‐retained, aberrant proteins by small membrane permeable molecules called pharmacological chaperones. Pharmacological chaperones can bind to misfolded proteins, including G‐protein coupled receptors (GPCRs), and promote their correct folding and export from the ER. Recently, common structural features of GPCRs have been uncovered, including the eighth helical domain in the C‐terminal tail and conserved residues in the transmembrane domains. However, little is known about the importance of these features in signaling and intracellular trafficking, because receptors deficient in these domains are likely retained in the ER due to misfolding. In this review, we summarize the current knowledge about the requirement of these consensus domains and amino acid residues for the passing through the quality control of the ER. Furthermore, we propose the utilization of membrane permeable ligands for the transport of their cognate, ER‐retained GPCRs to the cell surface. The chaperone activity of these ligands allows us to perform functional analyses of the structure‐deficient receptors after their trafficking to the cell surface. © 2010 IUBMB IUBMB Life, 62(6): 457–463, 2010