Slotkin T A, Lau C, Seidler F J
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Toxicol Appl Pharmacol. 1994 Dec;129(2):223-34. doi: 10.1006/taap.1994.1247.
Biogenic amines are hypothesized to play a role in the control of cell differentiation. We assessed the development of beta-adrenergic receptors and their linkage to adenylate cyclase activity in order to determine whether catecholaminergic cell signaling can take place early in development. On Gestational Day 12, beta-receptors were present in rat embryo in concentrations comparable to those in mature adrenergic target tissues; the concentrations climbed fivefold by Gestational Day 18. beta-Receptor expression was higher in liver than in heart and brain, as identified both by binding to isolated membrane preparations and by receptor autoradiography; nevertheless, receptor distribution was quite widespread, with labeling visible throughout the fetus. Receptor subtype selectivities (beta 2 in liver, beta 1 in heart, predominantly beta 2 in whole fetus) were already in place in early development, but receptor coupling to adenylate cyclase via G-proteins showed substantial developmental changes. Agonist-induced displacement of radioligand binding showed little or no GTP sensitivity on Gestational Day 12, suggesting relatively poor receptor linkage to Gs. In contrast, by Day 18, GTP produced a large shift in the agonist displacement curve. Receptor stimulation of adenylate cyclase by isoproterenol also showed a developmental spike by Gestational Day 18; the pattern for isoproterenol stimulation was distinct from the ontogeny of adenylate cyclase itself and from stimulation by forskolin-Mn2+ (which bypasses the need for receptors or G-proteins) or by fluoride (which activates G-proteins nonselectively). Thus, beta-receptors are highly expressed during fetal development and the receptors are readily capable of modulating intracellular cAMP production. Fetal catecholamines, which are produced and released by the adrenal medulla, extraadrenal chromaffin tissue, and cells that transiently express adrenergic phenotype, can thus have a direct impact on the differentiation of a wide variety of cells.
生物胺被认为在细胞分化控制中发挥作用。我们评估了β - 肾上腺素能受体的发育及其与腺苷酸环化酶活性的联系，以确定儿茶酚胺能细胞信号传导是否能在发育早期发生。在妊娠第12天，大鼠胚胎中的β - 受体浓度与成熟肾上腺素能靶组织中的浓度相当；到妊娠第18天，浓度上升了五倍。通过与分离的膜制剂结合以及受体放射自显影鉴定，肝脏中的β - 受体表达高于心脏和大脑；然而，受体分布相当广泛，整个胎儿体内都可见标记。受体亚型选择性（肝脏中为β2，心脏中为β1，整个胎儿中主要为β2）在发育早期就已确定，但受体通过G蛋白与腺苷酸环化酶的偶联显示出显著的发育变化。激动剂诱导的放射性配体结合置换在妊娠第12天对GTP几乎没有或没有敏感性，表明受体与Gs的联系相对较差。相比之下，到第18天，GTP使激动剂置换曲线发生了很大变化。异丙肾上腺素对腺苷酸环化酶的受体刺激在妊娠第18天也出现了发育高峰；异丙肾上腺素刺激的模式与腺苷酸环化酶本身的个体发育以及福斯高林 - Mn2 +（其绕过了对受体或G蛋白的需求）或氟化物（其非选择性激活G蛋白）刺激的模式不同。因此，β - 受体在胎儿发育期间高度表达，并且这些受体能够轻易调节细胞内cAMP的产生。由肾上腺髓质、肾上腺外嗜铬组织以及短暂表达肾上腺素能表型的细胞产生和释放的胎儿儿茶酚胺，因此可以对多种细胞的分化产生直接影响。
