The post-endocytotic fate of the gonadotropin receptors is an important determinant of the desensitization of gonadotropin responses

Abstract

Internalization of the ligand/receptor complexes is a consequence of the activation of the gonadotropin receptors. Since the recycling or degradation of the internalized receptors results in the maintenance or loss of cell surface receptors respectively and this contributes to the loss of responsiveness, we hypothesized that the fate of the internalized receptors could be an important component of desensitization. We examined this hypothesis using the wild-type and mutants of the human LH (hLHR) receptors and follitropin receptors expressed in MA-10 and KK-1 cells respectively. The receptor mutants were chosen because they are routed mostly to a lysosomal degradation pathway whereas the wild-type receptors are recycled back to the surface. We have shown that agonist stimulation of cells expressing the mutant receptors results in a more pronounced loss of cell surface receptors and agonist responses than stimulation of cells expressing the wild-type receptors. We concluded that receptor recycling promotes the maintenance of cell surface receptors and preserves hormonal responsiveness. This property of the hLHR is likely to be physiologically important because there at least two hLHR-expressing tissues in pregnant women, the maternal corpus luteum and the fetal Leydig cells, where a loss of hormonal responsiveness induced by the elevated levels of human chorionic gonadotropin that occur during pregnancy is not desirable.

Hypoglycosylated hFSH Has Greater Bioactivity Than Fully Glycosylated Recombinant hFSH in Human Granulosa Cells

“…The relative ability of FSH glycoforms to bind the FSHR was not affected by the numbers of FSHR present in the ligand-binding assay, since testis homogenates and CHO cells, which overexpress the FSHR, represent conditions of low vs high receptor density, respectively. This information is useful for the present analysis since others have shown that cellular signaling responses to FSH, such as cAMP accumulation (26), are proportional to the number of occupied receptors. It seems, therefore, that the extent of FSH␤ subunit N-glycosylation may contribute to the ability of FSH to activate the cAMP/PKA signaling pathway in granulosa cells.…”

Luteinizing hormone/chorionic gonadotrophin receptor overexpressed in granulosa cells from polycystic ovary syndrome ovaries is functionally active

“…Therefore it is possible that cytohesin 2 mediates ARF6 activation downstream of LHCGR. LHCGR internalises following its activation, which regulates the biological responsiveness of the receptor (Bhaskaran and Ascoli, 2005). The inhibition of LHCGR internalisation increases the density of cell surface receptors and thereby AC activation with consequent increase in cAMP accumulation.…”

“…LHCGR internalisation and recycling regulate the density of cell surface receptors and thereby the sensitivity of the cells to LH (Bhaskaran and Ascoli, 2005). ARF6 is a member of the ARF family of small GTPases, which regulates membrane trafficking by cycling between the active GTP-and inactive GDP-bound states (Donaldson and Jackson, 2011).…”

ARF6 Activated by the LHCG Receptor through the Cytohesin Family of Guanine Nucleotide Exchange Factors Mediates the Receptor Internalization and Signaling

“…An important aspect of LHCGR activity and its regulation is the internalization of agonist-activated receptors into the intracellular compartments of the cell (48). ARF6 regulates the internalization of LHCGR as well as that of other GPCRs (11,22), however, the molecular mechanisms underlying ARF6 involvement in GPCR trafficking are not well understood.…”