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Endocrinology. 2000 Jan;141(1):299-306.

The rat gonadotropin-releasing hormone receptor internalizes via a beta-arrestin-independent, but dynamin-dependent, pathway: addition of a carboxyl-terminal tail confers beta-arrestin dependency.

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  • 1Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology, Edinburgh, United Kingdom.


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 beta-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 beta-arrestin in COS-7 cells expressing each of the receptor constructs substantially increased endocytosis rate constants (k(e)) 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 beta-arrestin-promoted increase in the k(e) value was diminished by cotransfecting cells with the dominant negative beta-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 beta-arrestin-1- or beta-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 beta-arrestin dependency, indicating that they internalize via a clathrin-mediated pathway. We conclude that the mammalian GnRH-R uses a beta-arrestin-independent, dynamin-dependent internalization mechanism distinct from that employed by the other receptors studied.

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