Evidence that oestradiol attenuates beta-adrenoceptor function in the hypothalamus of female rats by altering receptor phosphorylation and sequestration.
Evidence that oestradiol attenuates beta-adrenoceptor function in the hypothalamus of female rats by altering receptor phosphorylation and sequestration.
复制标题
有证据表明雌二醇通过改变受体磷酸化和隔离来减弱雌性大鼠下丘脑的 β-肾上腺素受体功能。
DOI：
10.1046/j.1365-2826.2000.00562.x
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发表时间：
2000
影响因子：
3.2
通讯作者：
Etgen,AM
中科院分区：
文献类型：
--
作者：
Ansonoff,MA;Etgen,AM
下丘脑 (HYP) 和视前区 (POA) β-肾上腺素受体的激活会抑制雌性大鼠的促性腺激素释放和生殖行为。雌性大鼠暴露于生理相关剂量的雌激素 48 小时会减弱 HYP 和 POA 中的 β 肾上腺素受体功能，如异丙肾上腺素（β 肾上腺素受体激动剂）对腺苷酸环化酶活性的刺激减少所示。暴露于雌激素的雌性大鼠的 HYP-POA 中 β 肾上腺素受体与 G 蛋白的偶联减少与 β 肾上腺素受体功能的减弱相关。为了研究受体-G 蛋白解偶联的潜在机制，最初的实验测试了雌激素对 HYP 和 POA 中 β-肾上腺素受体功能的减弱涉及受体磷酸化的假设。用鱼精蛋白激活内源性丝氨酸/苏氨酸磷酸酶可将雌激素暴露雌性大鼠 HYP 切片中激动剂刺激的 cAMP 积累恢复至对照水平。其他实验检查了雌激素诱导的 β-肾上腺素受体结合密度和/或亚细胞定位的变化是否与 HYP 和 POA 中 β-肾上腺素受体功能的减弱相关。雌激素治疗不会改变 HYP 或 POA 中总 β-肾上腺素受体结合密度。然而，雌激素显着减少亲水性 β-肾上腺素受体拮抗剂 [3H] CGP 12177 与完整 HYP 和 POA 切片的细胞表面结合。同时，雌激素降低了蔗糖密度梯度离心后位于轻质囊泡部分的β-肾上腺素受体的比例。因此，雌激素通过将 β-肾上腺素受体与 G 蛋白解偶联，可能通过促进受体磷酸化来减弱 HYP-POA 中的 β-肾上腺素受体信号传导。此外，HYP 和 POA 中的很大一部分 β 肾上腺素受体不再能被亲水性配体接触，但不会被内化。因此，生理剂量的雌激素可能通过稳定 HYP 和 POA 中的 β-肾上腺素受体磷酸化，从而使受体与 G 蛋白解偶联，从而促进生殖行为和促性腺激素释放。
Activation of β‐adrenoceptors in the hypothalamus (HYP) and preoptic area (POA) inhibits both gonadotropin release and reproductive behaviour in female rats. Exposure of female rats for 48 h to physiologically relevant doses of oestrogen attenuates β‐adrenoceptor function in the HYP and POA as indicated by reduced isoproterenol (β‐adrenoceptor agonist) stimulation of adenylyl cyclase activity. Reduced β‐adrenoceptor coupling to G protein in the HYP‐POA from oestrogen‐exposed female rats correlates with attenuation of β‐adrenoceptor function. To examine potential mechanisms underlying receptor‐G protein uncoupling, initial experiments tested the hypothesis that oestrogen attenuation of β‐adrenoceptor function in the HYP and POA involves receptor phosphorylation. Activation of endogenous serine/threonine phosphatases with protamine restores agonist‐stimulated cAMP accumulation in HYP slices from oestrogen‐exposed female rats to control levels. Additional experiments examined whether oestrogen‐induced changes in β‐adrenoceptor binding density and/or subcellular localization correlate with the attenuation of β‐adrenoceptor function in the HYP and POA. Oestrogen treatment does not alter total β‐adrenoceptor binding density in the HYP or POA. However, oestrogen significantly reduces cell surface binding of the hydrophilic β‐adrenoceptor antagonist [3H] CGP 12177 to intact HYP and POA slices. At the same time, oestrogen decreases the fraction of β‐adrenoceptors localized in a light vesicle fraction following sucrose density gradient centrifugation. Therefore, oestrogen attenuates β‐adrenoceptor signalling in the HYP‐POA by uncoupling the β‐adrenoceptor from G protein, perhaps by promoting receptor phosphorylation. Furthermore, a significant fraction of β‐adrenoceptors in the HYP and POA are no longer accessible to hydrophilic ligands, but are not internalized. Thus, physiological doses of oestrogen may facilitate reproductive behaviour and gonadotropin release, in part, by stabilizing β‐adrenoceptor phosphorylation in the HYP and POA, thereby uncoupling the receptors from G protein.