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J. Biol. Chem., Vol. 276, Issue 43, 39685-39694, October 26, 2001
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From the Desensitization and internalization
of G-protein-coupled receptors can reflect receptor
phosphorylation-dependent binding of
Differential Internalization of Mammalian and Non-mammalian
Gonadotropin-releasing Hormone Receptors
UNCOUPLING OF DYNAMIN-DEPENDENT INTERNALIZATION FROM
MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING*
,,,,,
University Research Centre for
Neuroendocrinology, University of Bristol, Bristol, BS2 8HW, United
Kingdom, the ¶ Medical Research Council Human Reproductive
Sciences Unit, Edinburgh EH3 9ET, Scotland, and the
§ Medical Research Council Unit for Molecular Reproductive
Endocrinology, Department of Medical Biochemistry, University of Cape
Town, Observatory 7925, South Africa
-arrestin, which
prevents G-protein activation and targets receptors for internalization
via clathrin-coated vesicles. These can be pinched off by a dynamin
collar, and proteins controlling receptor internalization can also
mediate mitogen-activated protein kinase signaling.
Gonadotropin-releasing hormone (GnRH) stimulates internalization of its
receptors via clathrin-coated vesicles. Mammalian GnRH receptors
(GnRH-Rs) are unique in that they lack C-terminal tails and do not
rapidly desensitize, whereas non-mammalian GnRH-R have C-terminal tails
and, where investigated, do rapidly desensitize and internalize. Using
recombinant adenovirus expressing human and Xenopus GnRH-Rs
we have explored the relationship between receptor internalization and
mitogen-activated protein kinase signaling in HeLa cells with regulated
tetracycline-controlled expression of wild-type or a dominant
negative mutant (K44A) of dynamin. These receptors were phospholipase
C-coupled and had appropriate ligand affinity and specificity. K44A
dynamin expression did not alter human GnRH-R internalization but
dramatically reduced internalization of Xenopus GnRH-R (and
epidermal growth factor (EGF) receptor). Blockade of clathrin-mediated
internalization (sucrose) abolished internalization of all three
receptors. Both GnRH-Rs also mediated phosphorylation of ERK 2 and for
both receptors, this was inhibited by K44A dynamin. The same was true
for EGF- and protein kinase C-mediated ERK 2 phosphorylation. ERK 2 phosphorylation was also inhibited by a protein kinase C inhibitor but
not affected by an EGF receptor tyrosine kinase inhibitor. We conclude
that a) desensitizing and non-desensitizing GnRH-Rs are targeted for clathrin-coated vesicle-mediated internalization by functionally distinct mechanisms, b) GnRH-R signaling to ERK 2 is
dynamin-dependent and c) this does not reflect a dependence
on dynamin-dependent GnRH-R internalization.
*
This work was supported by the Wellcome Trust Project Grant
054949 (to C. A. M.) and by a Medical Research Council
Postgraduate Studentship 6046 (to J.H.).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. Tel.:
44-117-928-4570; Fax: 44-117-928-2080; E-mail:
craig.mcardle@bris.ac.uk.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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