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(Received for publication, May 23, 1996, and in revised form, June 21, 1996)
From the Gonadotropin receptors are members of the
seven-transmembrane (TM) receptor family. Several point mutations in TM
V and VI and the intracellular loop 3 (i3) have been identified in the
luteinizing hormone (LH) receptor gene, leading to constitutive
activation of the receptor. Because gonadotropin receptors are highly
conserved, we mutated the follicle-stimulating hormone (FSH) receptor
at the corresponding amino acids. However, the FSH receptor mutants
showed minimal increases in basal cAMP production. Taking advantage of
this difference between the two receptors, we designed chimeric
receptors with or without a point mutation in the i3 to identify the
region in the LH receptor important for its constitutive activation.
Introduction of the point mutation into chimeric receptors containing
only TM V to VI from the LH receptor led to major increases in
ligand-independent cAMP production. Furthermore, a chimeric receptor
with only TM V and VI derived from the LH receptor can be rendered
constitutively active by the mutation in the i3 from the FSH receptor.
These results suggest that interactions between TM V and VI of the FSH
receptor are essential for maintaining the receptor in the more
constrained state, whereas interactions between these domains of the LH
receptor are permissive for constitutively activating mutations in the
i3.
Volume 271, Number 37,
Issue of September 13, 1996
pp. 22470-22478
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
Division of Reproductive Biology, the
Department of Obstetrics and Gynecology, and the ¶ Howard Hugh
Medical Institute, Stanford University Medical School,
Stanford, California 94305
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