Abstract
The cytoplasmic C terminus of the beta2-adrenergic receptor and many
other G protein-coupled receptors contains a dileucine sequence that
has been implicated in endosome/lysosome targeting of diverse proteins.
In the present study, we provide evidence for an essential role of
this motif in the agonist-induced internalization of the beta2-adrenergic
receptor. Mutation of Leu-339 and/or Leu-340 to Ala caused little
changes in surface expression, ligand binding, G protein coupling,
and signaling to adenylyl cyclase, when these receptors were transiently
or stably expressed in CHO or HEK-293 cells. However, agonist-induced
receptor internalization was markedly impaired in the L339,340A double
mutant and reduced in the two single mutants. This impairment in
receptor internalization was seen by using various approaches to
determine internalization: binding of hydrophobic vs. hydrophilic
ligands, loss of surface beta2-adrenergic receptor immunoreactivity,
and immunofluorescence microscopy. The selective effects of these
mutations suggest that the C-terminal dileucine motif is involved
in agonist-induced internalization of the beta2-adrenergic receptor.
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