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J. Biol. Chem., Vol. 277, Issue 52, 50589-50596, December 27, 2002
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From the Departments of Pharmacology, Vanderbilt University Medical
Center, Nashville, Tennessee 37232-6600
The present studies demonstrate that no single
stretch of sequence in the third intracellular (3i) loop of the
Regulated Interactions of the
2A Adrenergic
Receptor with Spinophilin, 14-3-3
, and Arrestin 3*
2A adrenergic receptor (2A-AR) can
fully account for its previously described interactions with
spinophilin (Richman, J. G., Brady, A. E., Wang, Q., Hensel,
J. L., Colbran, R. J., and Limbird, L. E. (2001)
J. Biol. Chem. 276, 15003-15008), 14-3-3
(Prezeau,
L., Richman, J. G., Edwards, S. W., and Limbird, L. E. (1999) J. Biol. Chem. 274, 13462-13469), and arrestin
3 (Wu, G., Krupnick, J. G., Benovic, J. L., and Lanier,
S. M. (1997) J. Biol. Chem. 272, 17836-17842), suggesting that a three-dimensional surface, rather than a linear sequence, provides the basis for these interactions as proposed for 3i
loop tethering of the 2A-AR to the basolateral surface of Madin-Darby canine kidney cells (Edwards, S. W., and
Limbird, L. E. (1999) J. Biol. Chem. 274, 16331-16336). Sequences at the extreme N-terminal and C-terminal ends
of the 3i loop are critical for interaction with spinophilin but not
for interaction with 14-3-3 or arrestin 3, for which the C-terminal
half of the loop is more important. Competition binding for
35S-labeled 2A-AR 3i loop binding to
glutathione S-transferase (GST)-spinophilin amino acids
151-444 revealed a relative affinity of spinophilin 
arrestin > 14-3-3 for the unphosphorylated
2A-AR 3i loop. Agonist occupancy of the
2A-AR increases receptor association with spinophilin,
and arrestin 3 appears to compete for this enrichment. However, when
the G protein-coupled receptor kinase 2 substrate sequence was deleted
from the 3i loop, arrestin 3 could not compete for the agonist-enriched
binding of spinophilin to the mutant 2A-AR. These data
are consistent with a model where sequential or competitive
interactions among spinophilin, arrestin, and/or 14-3-3 play a role
in 2A-AR functions.
*
This research was supported by National Institutes of Health
Grant DK43879.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pharmacology,
Vanderbilt University Medical Center, 464 Robinson Research Bldg.,
Nashville, TN 37232-6600. Tel.: 615-322-2209; Fax: 615-322-6379; E-mail: lee.limbird@mcmail.vanderbilt.edu.
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