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Vol. 54, Issue 3, 525-535, September 1998
Forschungsinstitut für Molekulare Pharmakologie, D-10315
Berlin, Germany (R.S., R.H., A.O., B.W., G.K., W.R.), and
Rudolf-Buchheim-Institut für Pharmakologie, D-35392 Giessen,
Germany (M.D.)
Little is known concerning the intracellular transport of the G
protein-coupled receptors (GPCRs). Previous studies suggested a
functional role for those residues immediately preceding the conserved
palmitoylated cysteine residues in the intracellular carboxyl termini
of some GPCRs in cell surface transport. For the human vasopressin
V2 receptor, we assessed the significance of a dileucine
sequence with an upstream glutamate residue
(ELRSLLCC) in mediating cell surface delivery.
A series of deletion and point mutants in this region were constructed,
and the mutant receptors were expressed in transiently transfected
COS.M6 cells. By using [3H]arginine vasopressin binding
assays to intact cells and immunofluorescence studies with intact and
permeabilized cells, we show that residues E335 (mutant E335Q) and L339
(mutant L339T) are obligatory for receptor transport to the plasma
membrane. Residue L340 has a minor but significant influence.
[3H]Arginine vasopressin binding experiments on membranes
of lysed cells failed to detect any intracellular binding sites for the transport-deficient mutant receptors, suggesting that residues E335 and
L339 participate in receptor folding. Studies with green fluorescent
protein-tagged receptors demonstrate that the bulk of the mutant
receptors E335Q and L339T are trapped in the endoplasmic reticulum.
Complex glycosylation was absent in these mutant receptors, supporting
this conclusion. These data demonstrate that the glutamate/dileucine motif of the vasopressin V2 receptor is critical for the
escape of the receptor from the endoplasmic reticulum, most presumably by establishing a functional and transport-competent folding state. A
databank analysis revealed that these residues are part of a conserved
region in the GPCR family.
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