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Endocrinology Vol. 141, No. 1 299-306
Copyright © 2000 by The Endocrine Society

ARTICLES

The Rat Gonadotropin-Releasing Hormone Receptor Internalizes via a ß-Arrestin-Independent, but Dynamin-Dependent, Pathway: Addition of a Carboxyl-Terminal Tail Confers ß-Arrestin Dependency

Anders Heding1, Milka Vrecl1,2, Aylin C. Hanyaloglu, Robin Sellar, Philip L. Taylor and Karin A. Eidne

Medical Research Council Reproductive Biology Unit (A.H., M.V., A.C.H., R.S., P.L.T.), Center for Reproductive Biology, Edinburgh, United Kingdom EH3 9EW; and Western Australian Institute for Medical Research and Keogh Institute for Medical Research (K.E.), Sir Charles Gairdner Hospital, Perth 6009, Australia

Address all correspondence and requests for reprints to: Dr. K. A. Eidne, Western Australian Institute for Medical Research, Ground Floor, B Block QE II Medical Centre, Nedlands, Perth 6009, Australia. E-mail: keidne{at}waimr.uwa.edu.au

This study examined the mechanism underlying the rat GnRH receptor (GnRH-R) internalization pathway by investigating the role of added/extended C-terminal tails and the effect of ß-arrestins and dynamin. The internalization of the wild-type (WT) rat GnRH-R, stop codon mutants, GnRH-R/TRH receptor (TRH-R) chimera, rat TRH-R, and catfish GnRH-R was examined using radioligand binding assay. Overexpression of ß-arrestin in COS-7 cells expressing each of the receptor constructs substantially increased endocytosis rate constants (ke) of the TRH-R, catfish GnRH-R, and GnRH-R/TRH-R chimera, but not of the WT rat GnRH-R and stop codon mutants. The ß-arrestin-promoted increase in the ke value was diminished by cotransfecting cells with the dominant negative ß-arrestin-(319–418) mutant, whereas WT GnRH-R and stop codon mutant internalization were unaffected. Additionally, confocal microscopy showed that activated GnRH-Rs failed to induce time-dependent redistribution of either ß-arrestin-1- or ß-arrestin-2-green fluorescent protein conjugate to the plasma membrane. However, the dominant negative dynamin (DynK44A) mutant impaired internalization of all of the receptors regardless of their ß-arrestin dependency, indicating that they internalize via a clathrin-mediated pathway. We conclude that the mammalian GnRH-R uses a ß-arrestin-independent, dynamin-dependent internalization mechanism distinct from that employed by the other receptors studied.




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