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J Biol Chem, Vol. 273, Issue 52, 34911-34919, December 25, 1998
From the Departments of Previous results from this laboratory suggested
that the same active conformation of the lutropin/choriogonadotropin
receptor (LHR) is involved in the stimulation of G proteins and in
triggering the internalization of the bound agonist.
We have now analyzed two naturally occurring, constitutively active
mutants of the human LHR. These mutations were introduced into the rat
LHR (rLHR) and are designated L435R and D556Y. Cells expressing
rLHR-D556Y bind human choriogonadotropin (hCG) with normal affinity,
exhibit a 25-fold increase in basal cAMP and respond to hCG with a
normal increase in cAMP accumulation. This mutation does not affect the
internalization of the free receptor, but it enhances the
internalization of the agonist-occupied receptors ~3-fold. Cells
expressing rLHR-L435R also bind hCG with normal affinity, exhibit a
47-fold increase in basal cAMP, and do not respond to hCG with a
further increase in cAMP accumulation. This mutation enhances the
internalization of the free and agonist-occupied receptors ~2- and
~17-fold, respectively. We conclude that the state of activation of
the rLHR can modulate its basal and/or agonist-stimulated internalization.
Since the internalization of hCG is involved in the termination of hCG
actions, we suggest that the lack of responsiveness detected in cells
expressing rLHR-L435R is due to the fast rate of internalization of the
bound hCG. The finding that membranes expressing rLHR-L435R (a system
where internalization does not occur) respond to hCG with an increase
in adenylyl cyclase activity supports this suggestion.
Mutations That Induce Constitutive Activation and Mutations
That Impair Signal Transduction Modulate the Basal and/or
Agonist-stimulated Internalization of the Lutropin/Choriogonadotropin
Receptor
,,,,
Pharmacology and
§ Physiology and Biophysics, University of Iowa College of
Medicine, Iowa City, Iowa 52242-1109
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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