Postendocytotic Trafficking of the Follicle-Stimulating Hormone (FSH)-FSH Receptor Complex

Abstract

Although the fates of the internalized hormone-receptor complexes formed by the lutropin/choriogonadotropin and the TSH receptors have been examined in some detail, much less is known about the fate of the internalized FSH-FSH receptor (FSHR) complex. Using biochemical and imaging approaches we show here that the majority of the internalized FSH-FSHR complex accumulates in endosomes and subsequently recycles back to the cell surface where the bound, intact hormone dissociates back into the medium. Only small amounts of FSH and the FSHR are routed to a lysosomal degradation pathway, and the extent of FSH-induced down-regulation of the cell surface and total FSHR is minimal. This pathway was detected in heterologous (human kidney 293T) cells transfected with the rat (r) or human (h) FSHR as well as in a mouse Sertoli cell line (MSC-1) or a mouse granulosa cell line (KK-1) transfected with the rFSHR.Additional experiments using a series of C-terminal deletions of the rFSHR and the hFSHR showed that the recycling of the internalized FSH-FSHR complex and the extent of hFSH-induced down-regulation is dictated by a short stretch of amino acids present at the extreme C-terminal end of the receptor.We conclude that most of the internalized FSH-FSHR complex is recycled back to the cell surface, that this recycling pathway is highly dependent on amino acid residues present near the C terminus of the FSHR, and that it is an important determinant of the extent of down-regulation of the FSHR.

Differential time course of FSH/FSH receptor complex endocytosis within sertoli and germ cells during rat testis development

“…However, the present findings and the lack of detectable FSH-gold particles within the recycling endosomal compartment differ from the results of Krishnamurthy et al (2003) who demonstrated that most of the FSH/FSH-R complex could be recycled to the plasma membrane. The reasons for this discrepancy are presently unknown.…”

GIPC Binds to the Human Lutropin Receptor (hLHR) through an Unusual PDZ Domain Binding Motif, and It Regulates the Sorting of the Internalized Human Choriogonadotropin and the Density of Cell Surface hLHR

“…Functional Consequences of the hLHR/GIPC Interaction-A substantial portion of the hCG that is internalized by the hLHR is recycled back to the medium as undegraded hormone, and the density of cell surface hLHR remains relatively constant during many rounds of endocytosis of hCG (12,13,30). Both of these phenomena are dependent on the presence of Leu 683 and the C-terminal Cys 699 of the hLHR (Tables I and II).…”

“…internalized by the hLHR is recycled back to the medium in an undegraded form (13,26,30), the internalized hLHR localizes mostly to endosomes (13), and the loss of cell surface hLHR during the endocytosis of hCG in cells expressing the recombinant hLHR is minimal (13).…”

“…This was defined as t ϭ 0, and the cells (which now contain only internalized 125 I-hCG) were incubated for an additional 2 h at 37°C in medium containing an excess of non-radioactive hCG (4 g/ml). These conditions facilitate the detection of the recycled hormone by preventing the reassociation of the recycled and released hCG with the receptor (30). At the end of this second incubation the medium was saved, and the cells were washed with cold medium.…”

A Novel Sorting Sequence in the β2-Adrenergic Receptor Switches Recycling from Default to the Hrs-dependent Mechanism

“…There is increasing evidence that a number of GPCRs require specific structural determinant(s) within their cytoplasmic domains in order to undergo efficient recycling to the plasma membrane (5)(6)(7)(8)(9)(10)(11). This process of "sequence-directed" recycling differs from "default" recycling of many other integral membrane proteins, such as the transferrin receptor, which occurs in the absence of any known cytoplasmic determinant and apparently by bulk membrane flow (12,13).…”