Anterograde trafficking of G protein-coupled receptors: Function of the C-terminal F(X) 6LL motif in export from the endoplasmic reticulum

Matthew T. Duvernay, Chunmin Dong, Xiaoping Zhang, Fuguo Zhou, Charles D. Nichols, Guangyu Wu

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


We have reported previously that the F(X) 6LL motif in the C termini is essential for export of aα 2B-adrenergic (α 2B-AR) and angiotensin II type 1 receptors (AT1Rs) from the endoplasmic reticulum (ER). Here, we further demonstrate that mutation of the F(X) 6lL motif similarly abolished the cell-surface expression of α 2B-AR, AT1R, α 1B-AR, and β 2- AR, suggesting that the F(X) 6LL motif plays a general role in ER export of G protein- coupled receptors (GPCRs). Mutation of Phe to Val, Leu, Trp, and Tyr, and mutation of LL to FF and VV, markedly inhibited α 2B-AR transport, indicating that the F(X) 6LL function cannot be fully substituted by other hydrophobic residues. The structural analysis revealed that the Phe residue in the F(X) 6LL motif is buried in the transmembrane domains and possibly interacts with Ile58 in β 2-AR and Val42 in α 2B-AR, whereas the LL motif is exposed to the cytosolic space. Indeed, mutation of Ile58 in β 2-AR and Val42 in α 2B-AR markedly disrupted cell surface transport of the receptors. It is noteworthy that the Val and Ile residues are highly conserved among the GPCRs carrying the F(X) 6LL motif. Furthermore, the Phe mutant exhibited a stronger interaction with ER chaperones and was more potently rescued by physical and chemical treatments than the LL mutant. These data suggest that the Phe residue is probably involved in folding of α 2B-AR and β 2-AR, possibly through interaction with other hydrophobic residues in neighboring domains. These data also provide the first evidence implying crucial roles of the C termini possibly through modulating multiple events in an- terograde trafficking of GPCRs.

Original languageEnglish (US)
Pages (from-to)751-761
Number of pages11
JournalMolecular pharmacology
Issue number4
StatePublished - Apr 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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