Ansonoff M A, Etgen A M
Department of Neuroscience, Albert Einstein College of Medicine, Bronx 10461, NY, USA.
J Neuroendocrinol. 2000 Nov;12(11):1060-6. doi: 10.1046/j.1365-2826.2000.00562.x.
Activation of beta-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 beta-adrenoceptor function in the HYP and POA as indicated by reduced isoproterenol (beta-adrenoceptor agonist) stimulation of adenylyl cyclase activity. Reduced beta-adrenoceptor coupling to G protein in the HYP-POA from oestrogen-exposed female rats correlates with attenuation of beta-adrenoceptor function. To examine potential mechanisms underlying receptor-G protein uncoupling, initial experiments tested the hypothesis that oestrogen attenuation of beta-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 beta-adrenoceptor binding density and/or subcellular localization correlate with the attenuation of beta-adrenoceptor function in the HYP and POA. Oestrogen treatment does not alter total beta-adrenoceptor binding density in the HYP or POA. However, oestrogen significantly reduces cell surface binding of the hydrophilic beta-adrenoceptor antagonist [3H] CGP 12177 to intact HYP and POA slices. At the same time, oestrogen decreases the fraction of beta-adrenoceptors localized in a light vesicle fraction following sucrose density gradient centrifugation. Therefore, oestrogen attenuates beta-adrenoceptor signalling in the HYP-POA by uncoupling the beta-adrenoceptor from G protein, perhaps by promoting receptor phosphorylation. Furthermore, a significant fraction of beta-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 beta-adrenoceptor phosphorylation in the HYP and POA, thereby uncoupling the receptors from G protein.
下丘脑（HYP）和视前区（POA）中的β-肾上腺素能受体激活可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小时后，HYP和POA中的β-肾上腺素能受体功能减弱，这表现为异丙肾上腺素（β-肾上腺素能受体激动剂）对腺苷酸环化酶活性的刺激作用降低。雌激素处理的雌性大鼠HYP-POA中β-肾上腺素能受体与G蛋白的偶联减少与β-肾上腺素能受体功能减弱相关。为了研究受体-G蛋白解偶联的潜在机制，初步实验检验了以下假设：雌激素对HYP和POA中β-肾上腺素能受体功能的减弱涉及受体磷酸化。用鱼精蛋白激活内源性丝氨酸/苏氨酸磷酸酶可将雌激素处理的雌性大鼠HYP切片中激动剂刺激的cAMP积累恢复到对照水平。额外的实验研究了雌激素诱导的β-肾上腺素能受体结合密度和/或亚细胞定位变化是否与HYP和POA中β-肾上腺素能受体功能的减弱相关。雌激素处理不会改变HYP或POA中总的β-肾上腺素能受体结合密度。然而，雌激素显著降低了亲水性β-肾上腺素能受体拮抗剂[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囊泡部分的β-肾上腺素能受体比例。因此，雌激素通过使β-肾上腺素能受体与G蛋白解偶联，可能是通过促进受体磷酸化，来减弱HYP-POA中的β-肾上腺素能受体信号传导。此外，HYP和POA中相当一部分β-肾上腺素能受体不再能被亲水性配体识别，但并未被内化。因此，生理剂量的雌激素可能部分通过稳定HYP和POA中β-肾上腺素能受体的磷酸化，从而使受体与G蛋白解偶联，来促进生殖行为和促性腺激素释放。
