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J. Biol. Chem., Vol. 277, Issue 24, 21939-21946, June 14, 2002
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From the Department of Pharmacology, The University of Iowa College
of Medicine, Iowa City, Iowa 52242
The rat follitropin receptor (rFSHR) is an
unusual G protein-coupled receptor in that agonist-induced
activation leads to the phosphorylation of the first and third
intracellular loops instead of the C-terminal tail. To determine
regions of G protein-coupled receptors that affect internalization
independently of phosphorylation we examined the effects of truncations
of the C-terminal tail of the rFSHR on agonist-induced internalization.
Our studies show that progressive truncations of a region flanked by
residues 642 and 651 enhance the internalization of human
follicle-stimulating hormone (hFSH). Further characterization of a
mutant truncated at residue 649 (designated rFSHR-t649) and another
mutant in which the 642-651 region was deleted in the context of the
full-length rFSHR, designated rFSHR(
642-651), showed that both of
them internalized hFSH at rates that were 2-3 times faster than
rFSHR-wild type (wt). Like rFSHR-wt, however, the internalization of
hFSH mediated by rFSHR-t649 and rFSHR(
642-651) can be inhibited
with dominant-negative mutants of the non-visual arrestins or dynamin.
Alanine-scanning mutagenesis of the 642-651 region suggests that the
effects on internalization are not mediated by a single residue,
however. In an attempt to understand the molecular basis of the
enhanced internalization of hFSH mediated by these mutants we used an
assay that can be readily used to assess the association of the rFSHR with the arrestin-3 in co-transfected cells. Using this assay we were
able to show that, when compared with rFSHR-wt, rFSHR(
642-651) displays an ~4-fold enhancement in binding affinity for arrestin-3 and an ~1.7-fold reduction in maximal arrestin-3 binding capacity. We
conclude that a short linear sequence present in the C-terminal tail of
the rFSHR (642SATHNFHARK651) that is not
phosphorylated limits internalization by lowering the affinity of the
rFSHR for the endogenous non-visual arrestins.
To whom correspondence should be addressed: Dept. of Pharmacology,
2-319A BSB, 51 Newton Rd., The University of Iowa, Iowa City, IA
52242-1109. Tel.: 319-335-9907; Fax: 319-335-8930; E-mail: mario-ascoli@uiowa.edu.
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