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J. Biol. Chem., Vol. 277, Issue 39, 36577-36584, September 27, 2002
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From the Departments of Studies in many rhodopsin-like G-protein-coupled
receptors are providing a general scheme of the structural processes
underlying receptor activation. Microdomains in several receptors have
been identified that appear to function as activation switches.
However, evidence is emerging that these receptor proteins exist in
multiple conformational states. To study the molecular control of this switching process, we investigated the function of a microdomain involving the conserved helix 7 tyrosine in the serotonin 5HT2C receptor. This tyrosine of the NPXXY motif was
substituted for all naturally occurring amino acids. Three distinct
constitutively active receptor phenotypes were found: moderate, high,
and "locked-on" constitutive activity. In contrast to the activity
of the other receptor mutants, the high basal signaling of the
locked-on Y7.53N mutant was neither increased by agonists nor
decreased by inverse agonists. The Y7.53F mutant was uncoupled.
Computational modeling based on the rhodopsin crystal structure
suggested that Y7.53 interacts with the conserved aromatic ring at
position 7.60 in the recently identified helix 8 domain. This provided
a basis for seeking revertant mutations to correct the defective
function of the Y7.53F receptor. When the Y7.53F receptor was mutated
at position 7.60, the wild-type phenotype was restored. These results suggest that Y7.53 and Y7.60 contribute to a common functional microdomain connecting helices 7 and 8 that influences the switching of
the 5HT2C receptor among multiple active and inactive conformations.
Conserved Helix 7 Tyrosine Acts as a Multistate Conformational
Switch in the 5HT2C Receptor
IDENTIFICATION OF A NOVEL "LOCKED-ON" PHENOTYPE AND DOUBLE
REVERTANT MUTATIONS*
,,¶
**
Neurology,
§ Physiology and Biophysics, ¶ Pharmacology and
Biological Chemistry and the Fishberg Research Center for
Neurobiology, Mount Sinai School of Medicine, New York, New York
10029
*
This work was supported by Grant P01-DA12923 from the
National Institutes of Health.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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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