对生长激素释放因子（GRF）的脱敏作用与GRF结合位点的下调有关。

Desensitization to growth hormone-releasing factor (GRF) is associated with down-regulation of GRF-binding sites.

作者信息

Bilezikjian L M, Seifert H, Vale W

出版信息

Endocrinology. 1986 May;118(5):2045-52. doi: 10.1210/endo-118-5-2045.

DOI:10.1210/endo-118-5-2045

Abstract

The time course, concentration dependence, and mechanism of rat anterior pituitary desensitization to GRF were studied. Chronic stimulation of cultures of rat anterior pituitary cells with rat GRF (rGRF) resulted in desensitization to a subsequent challenge with the peptide. Despite a slight enhancement of GH synthesis, prolonged exposure to GRF caused substantial depletion of cellular GH pools. As a result, acute secretory responses were markedly blunted. Depletion was accompanied by a time-dependent decrease in sensitivity to rGRF; GRF EC50 values for GH release of 0.5 nM rGRF-pretreated cells were 24.8 +/- 6 (+/- SEM) pM after 2 h, 46.2 +/- 2.4 pM after 4 h, and 154.7 +/- 31 pM after 8 h compared to 9.2 +/- 0.6 pM for control cells. The process of desensitization was complete within 8 h, as cells pretreated for 24 h exhibited sensitivity to rGRF comparable to that of cells pretreated for 8 h. Desensitization was associated with a time-dependent decrease in rat anterior pituitary cell GRF-binding capacity; a 48% loss of binding sites was evident after a 2-h pretreatment with 0.5 nM rGRF, with a maximum loss occurring after 8 h. The dose of rGRF required to produce an attenuation of responsiveness did not completely correlate with the dose requirement for down-regulation of binding sites. The decrease in GRF-binding sites was not associated with any alteration of apparent Kd values, which were 0.36 (0.18-0.72) nM in control and 0.1 (0.01-0.82) nM after 8 h of exposure to 0.5 nM rGRF. Both the reduction in GRF-binding capacity and decreased sensitivity to GRF were reversible after 24 h, although cellular GH pools were not restored to control levels. These results suggest that rat anterior pituitary cells become desensitized to rGRF after chronic stimulation with a maximal concentration of the peptide. One mechanism for this decrease in apparent sensitivity to rGRF may be the pronounced reduction or down-regulation of GRF-binding sites.

摘要

研究了大鼠垂体前叶对生长激素释放因子（GRF）脱敏的时间进程、浓度依赖性及机制。用大鼠GRF（rGRF）长期刺激大鼠垂体前叶细胞培养物会导致对该肽随后刺激的脱敏。尽管生长激素（GH）合成略有增强，但长时间暴露于GRF会导致细胞内GH储备大量消耗。结果，急性分泌反应明显减弱。储备消耗伴随着对rGRF敏感性的时间依赖性降低；与对照细胞的9.2±0.6 pM相比，0.5 nM rGRF预处理细胞在2小时后GH释放的GRF EC50值为24.8±6（±SEM）pM，4小时后为46.2±2.4 pM，8小时后为154.7±31 pM。脱敏过程在8小时内完成，因为预处理24小时的细胞对rGRF的敏感性与预处理8小时的细胞相当。脱敏与大鼠垂体前叶细胞GRF结合能力的时间依赖性降低有关；用0.5 nM rGRF预处理2小时后，结合位点明显丧失48%，8小时后丧失最多。产生反应性减弱所需的rGRF剂量与结合位点下调的剂量要求并不完全相关。GRF结合位点的减少与表观解离常数（Kd）值的任何改变无关，对照中的Kd值为0.36（0.18 - 0.72）nM，暴露于0.5 nM rGRF 8小时后为0.1（0.01 - 0.82）nM。尽管细胞内GH储备未恢复到对照水平，但GRF结合能力的降低和对GRF敏感性的降低在24小时后均可逆转。这些结果表明，大鼠垂体前叶细胞在被该肽的最大浓度长期刺激后会对rGRF脱敏。对rGRF表观敏感性降低的一种机制可能是GRF结合位点的显著减少或下调。