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(Received for publication, January 22, 1997, and in revised form, May 13, 1997)
,
,
,
and
From the Internalization of a variety of different
heptahelical G protein-coupled receptors has been shown to be
influenced by a number of different structural determinants of the
receptors, including the carboxyl terminus. To investigate the role of
the carboxyl terminus of cholecystokinin (CCK) receptors in receptor
internalization, the rat wild type (WT) CCK-A receptor (WT CCKAR) and
the rat WT CCK-B receptor (WT CCKBR) were truncated after amino acid
residue 399 (CCKAR Tr399) and 408 (CCKBR Tr408), thereby deleting the carboxyl-terminal 45 and 44 residues, respectively. All WT and mutant
CCK receptors were stably expressed in NIH/3T3 cells. Internalization of the CCKAR Tr399 was not significantly different from the WT CCKAR.
In contrast, internalization of the CCKBR Tr408 was decreased to 26%
compared with the WT CCKBR internalization of 92%. The mutation of all
10 serine and threonine residues (as potential phosphorylation sites)
in the carboxyl terminus of the CCKBR to alanines (mutant CCKBR
Digestive Diseases Branch, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892 and
Molecular
Aspects of Drug Design Section, ABL-Basic Research Program,
NCI-Frederick Cancer Research and Development Center,
Frederick, Maryland 21702
S/T)
could account for the majority of this effect (39% internalization).
All mutant receptors displayed similar ligand binding characteristics,
G protein coupling, and signal transduction as their respective WT
receptors, indicating that the carboxyl termini are not necessary for
these processes. Thus, internalization of the CCKBR, unlike that of the
CCKAR, depends on the carboxyl terminus of the receptor. These results suggest that, despite the high degree of homology between CCKAR and
CCKBR, the structural determinants that mediate the interaction with
the endocytic pathway reside in different regions of the receptors.
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