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Phe27Cys Polymorphism Alters the Maturation and Subcellular Localization of the Human δ Opioid Receptor
Author(s) -
Leskelä Tarja T.,
Markkanen Piia M. H.,
Alahuhta Ilkka A.,
Tuusa Jussi T.,
PetäjäRepo Ulla E.
Publication year - 2009
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2008.00846.x
Subject(s) - biology , subcellular localization , receptor , opioid receptor , microbiology and biotechnology , opioid , polymorphism (computer science) , genetics , gene , computational biology , genotype
The human δ opioid receptor (hδOR) is a G‐protein‐coupled receptor that is mainly involved in the modulation of pain and mood. Only one nonsynonymous single nucleotide polymorphism (T80G) has been described, causing Phe27Cys substitution in the receptor N‐terminus and showing association with substance dependence. In this study, we expressed the two hδOR variants in a heterologous expression system with an identical genetic background. They differed greatly during early steps of biosynthesis, displaying a significant difference in the maturation efficiency (50% and 85% for the Cys27 and Phe27 variants, respectively). The Cys27 variant also showed accumulation in pre‐Golgi compartments of the secretory pathway and impaired targeting to endoplasmic reticulum (ER)‐associated degradation following long‐term expression. In addition, the cell surface receptors of the Cys27 variant internalized constitutively. Replacement of phenylalanine with other amino acids revealed that cysteine at position 27 decreased the mature receptor/precursor ratio most extensively, suggesting a thiol‐mediated retention of precursors in the ER. However, cysteine did not cause a major folding defect because pharmacological characteristics and the maturation kinetics of the variants were identical, and an opioid antagonist was able to enhance the maturation of both variants. We conclude that, instead of causing loss of function, Phe27Cys polymorphism of the hδOR causes a gain‐of‐function phenotype, which may have implications for the regulation of receptor expression at the cell surface and possibly also for the susceptibility to pathophysiological states.