Slotkin T A, Lappi S E, Seidler F J
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Toxicol Appl Pharmacol. 1995 Aug;133(2):188-95. doi: 10.1006/taap.1995.1141.
beta-Adrenergic receptors appear in noradrenergic target tissues well before the arrival of nerve terminals, and are thought to play a role in the control of cell differentiation. We examined the ability of beta-agonists to stimulate expression of the nuclear transcription factor, c-fos, in developing rat liver and heart. This factor has been shown to associated with trophic activation of genes involved in both cell differentiation and cell growth. In response to terbutaline, a beta 2-selective agonist, marked stimulation of c-fos was demonstrated in the liver, which contains beta 2-receptors, on Gestational Day 20, as well as on Postnatal Days 1 and 8. In the heart, which contains predominantly beta 1-receptors, isoproterenol (a non-subtype-selective beta-agonist) was more effective that terbutaline, indicating that either receptor subtype can elicit stimulation of c-fos. In both tissues, the response magnitude increased with age, rather than following changes in receptor number, which increase in the heart but decrease in the liver; the same pattern has been seen for the ability of beta-agonists to promote cell differentiation at the expense of replication; the implication is that ontogenetic changes in post-receptor coupling are much more important than is the number of receptors in determining neurotrophic influences on gene expression and cell development. In keeping with the view that fetal/neonatal beta-adrenergic stimulation of c-fos is related to cell differentiation rather than simply to growth, repeated administration of isoproterenol to neonatal rats did not elicit cardiac hypertrophy, whereas the same treatment did produce hypertrophy in adult rats. The intracellular signaling cascade from beta-receptor to c-fos expression may thus provide one of the basic cellular mechanisms for trophic control of differentiation by biogenic amines, and for the teratologies associated with beta-adrenergic agonist therapy.
β-肾上腺素能受体在神经末梢到达之前就已出现在去甲肾上腺素能靶组织中，被认为在细胞分化控制中发挥作用。我们研究了β-激动剂刺激发育中的大鼠肝脏和心脏中核转录因子c-fos表达的能力。该因子已被证明与参与细胞分化和细胞生长的基因的营养激活有关。在妊娠第20天以及出生后第1天和第8天，对含有β2-受体的肝脏给予β2-选择性激动剂特布他林后，可显著刺激c-fos表达。在主要含有β1-受体的心脏中，异丙肾上腺素（一种非亚型选择性β-激动剂）比特布他林更有效，这表明任何一种受体亚型都能引发对c-fos的刺激。在这两种组织中，反应强度随年龄增加，而不是随受体数量的变化，受体数量在心脏中增加而在肝脏中减少；β-激动剂以牺牲复制为代价促进细胞分化的能力也呈现相同模式；这意味着在决定对基因表达和细胞发育的神经营养影响方面，受体后偶联的个体发生变化比受体数量更为重要。与胎儿/新生儿β-肾上腺素能刺激c-fos与细胞分化而非简单的生长相关的观点一致，对新生大鼠反复给予异丙肾上腺素不会引起心脏肥大，而相同处理在成年大鼠中确实会导致肥大。从β-受体到c-fos表达的细胞内信号级联可能因此为生物胺对分化的营养控制以及与β-肾上腺素能激动剂治疗相关的致畸作用提供了一种基本的细胞机制。
