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J. Biol. Chem., Vol. 276, Issue 9, 6524-6528, March 2, 2001
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From the We have investigated the
participation of endogenous ADP-ribosylation factor (ARF)
nucleotide-binding site opener (ARNO) in desensitization of the
luteinizing hormone/choriogonadotropin (LH/CG) receptor, independent of
receptor internalization, using a cell-free plasma membrane model. We
recently showed that the addition of recombinant ARNO promotes binding
of
Desensitization of the Luteinizing Hormone/Choriogonadotropin
Receptor in Ovarian Follicular Membranes Is Inhibited by Catalytically
Inactive ARNO+*
,¶
Department of Cell and Molecular Biology,
Northwestern University Medical School, Chicago, Illinois 60611 and the
§ Department of Cell Biology, University of Virginia Health
Sciences Center, Charlottesville, Virginia 22908
-arrestin1 to the third intracellular (3i) loop of the active
LH/CG receptor, thereby reducing the ability of the receptor to
activate the stimulatory G protein and signal to adenylyl
cyclase. In the present report we determined whether ARNO is
detectable in follicular membranes and whether the catalytically
inactive E156K ARNO mutant, containing a mutation in the Sec7 domain,
can act in a dominant negative manner to block LH/CG receptor
desensitization. Results show that ARNO is readily detected in
follicular membranes and that levels of membrane-associated ARNO
increase with follicular maturation. The addition of catalytically
inactive E156K ARNO blocks both the release of -arrestin1 from its
membrane docking site, based on Western blot analysis, and development
of LH/CG receptor desensitization. We also investigated whether a point
mutation in the pleckstrin homology (PH) domain of ARNO (R280D),
which blocks binding of phosphoinositides like phosphatidylinositol
3,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate
(PIP2) but not catalytic activity, disrupts LH/CG receptor
desensitization. R280D ARNO neither promotes nor inhibits LH/CG
receptor desensitization, consistent with a requirement of the PH
domain of ARNO for its association with the plasma membrane. LH/CG
receptor activation of ARNO is not mediated by activation of
phosphatidylinositol 3-kinase (PI 3-kinase) or by G protein 
subunits. Taken together, these results suggest that LH/CG receptor
promotes -arrestin1 release from its membrane docking site to bind
to the 3i loop of the LH/CG receptor via activation of membrane
delimited endogenous ARNO. As ARNO activation is independent of PI
3-kinase and G, our results are consistent with a role for
PIP2 in receptor-stimulated ARNO activation.
*
This work was funded by National Institutes of Health Grants
R01 HD/DK 38060 (to M. H.-D.), and R01 AI 32991 (to J. E. C.) and by
a Lalor Foundation fellowship (to S. M.). Preliminary results were presented at the 82nd Annual Meeting of the Endocrine Society, Toronto, Canada, June 2000.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.
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