Inhibition of synthesis of luteinizing hormone (LH) receptors by a down-regulating dose of LH.

Although LH is known to cause down-regulation of the LH/human CG (hCG) receptor, the mechanisms underlying this process are not well understood. Here we have analyzed the effects of LH on the turnover of LH receptors in cultured granulosa cells. Down-regulation was stimulated in FSH-primed granulosa cells by exposure to LH for 1 h. By 24 h after LH exposure, the LH/hCG receptor content, as measured using [125I]iodo-hCG was 70% less than controls. To determine whether this loss of LH/hCG receptors was due to accelerated receptor degradation, turnover measurements were made using tunicamycin to inhibit LH/hCG receptor synthesis. Under these conditions, there was a small (16%) increase in the rate of degradation of LH/hCG receptors in LH-treated cells compared to controls. By contrast, the rate of LH/hCG receptor synthesis, estimated mathematically, was reduced by 75% in the LH-treated cells. LH treatment had no effect on the incorporation of [35S]methionine into total cellular protein. Withdrawing FSH from the culture medium had a similar effect, slightly enhancing LH/hCG receptor degradation while markedly reducing its synthesis. The role of lysosomes in the degradation of LH/hCG receptors was also investigated. The lysosomotropic amine NH4Cl failed to cause LH/hCG receptors to accumulate, contrary to what would be expected if LH/hCG receptors were degraded lysosomally. In contrast, NH4Cl inhibited the degradation of receptor-bound [125I]iodo-hCG, suggesting that the ligand and the receptor may be handled differently by the granulosa cell. Our results suggest that in the granulosa cell, LH down-regulates its own receptor by inhibiting the synthesis of LH/hCG receptors, possibly by interfering with the ability of FSH to stimulate the synthesis of LH/hCG receptors. Furthermore, they suggest that the degradation of LH/hCG receptors may occur by nonlysosomal mechanisms.