Slotkin T A, Saleh J L, Zhang J, Seidler F J
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USA.
Brain Res. 1996 Dec 2;742(1-2):317-28. doi: 10.1016/s0006-8993(96)00978-x.
The ability of adrenergic stimulation to elicit desensitization of the beta-receptor/adenylyl cyclase signaling cascade is not an inherent property of cells but rather is acquired during the period in which sympathetic innervation develops. This study examines whether innervation provides the signal that enables target cardiac and hepatic cells to learn to desensitize their responses. Neonatal rats were sympathectomized with 6-OHDA on postnatal day 1 and were treated at various ages with a regimen of isoproterenol known to elicit desensitization in adults. In control rats, desensitization first appeared between days 6 and 15. Desensitization was heterologous, involving changes in the efficiency of G-protein coupling, as there were parallel decreases in isoproterenol-stimulated adenylyl cyclase activity, basal activity and fluoride-stimulated activity (maximal G-protein activation) without changes in forskolin-Mn2+-stimulated activity (total cyclase catalytic activity). The lesioned animals showed a delay in the onset of desensitization as isoproterenol did not evoke decreased responsiveness until day 25 in the heart; the liver did not display agonist-induced desensitization even at day 25. The effects of lesioning on development of desensitization were entirely separable from those on regulation of beta-receptors themselves: agonist-induced decreases in receptor binding appeared by day 15 in both control and lesioned animals. Uniquely in the youngest animals (6 days old), isoproterenol treatment produced heterologous sensitization of adenylyl cyclase responses rather than desensitization, with a parallel increase in basal, isoproterenol-, fluoride- and forskolin-Mn2+-stimulated activity; the latter indicates induction of total catalytic activity as the primary mechanism of sensitization. The lesioned neonates did not show sensitization, despite the fact that during this period, sympathetic pathways are not functionally competent. Our results indicate that innervation provides a timing signal for the onset of desensitization capabilities of sympathetic target cells, but is not absolutely required for the cells to learn how to desensitize. Prior to the onset of desensitization, agonists induce sensitization that may be important in preserving physiological responsiveness during ontogenetic surges of adrenergic activity. The absence of sensitization in lesioned animals implies that, before physiological function is completely established, early pioneer synapses provide a trophic signal that enables cells to increase their sensitivity to stimulation during the perinatal transition period.
肾上腺素能刺激引发β受体/腺苷酸环化酶信号级联脱敏的能力并非细胞的固有特性，而是在交感神经支配发育期间获得的。本研究探讨神经支配是否提供信号，使靶心脏和肝细胞学会使其反应脱敏。新生大鼠在出生后第1天用6-羟基多巴胺进行交感神经切除术，并在不同年龄用已知能在成年大鼠中引发脱敏的异丙肾上腺素方案进行治疗。在对照大鼠中，脱敏首先出现在第6天至第15天之间。脱敏是异源的，涉及G蛋白偶联效率的变化，因为异丙肾上腺素刺激的腺苷酸环化酶活性、基础活性和氟化物刺激的活性（最大G蛋白激活）平行下降，而福斯可林-Mn2+刺激的活性（总环化酶催化活性）没有变化。受损动物的脱敏开始出现延迟，因为异丙肾上腺素直到心脏的第25天才引起反应性降低；即使在第25天，肝脏也未表现出激动剂诱导的脱敏。损伤对脱敏发育的影响与对β受体自身调节的影响完全可分离：在对照和受损动物中，激动剂诱导的受体结合减少在第15天出现。在最年幼的动物（6天大）中，异丙肾上腺素治疗独特地产生了腺苷酸环化酶反应的异源致敏而非脱敏，基础、异丙肾上腺素、氟化物和福斯可林-Mn2+刺激的活性平行增加；后者表明诱导总催化活性是致敏的主要机制。尽管在此期间交感神经通路功能不全，但受损的新生儿并未表现出致敏。我们的结果表明，神经支配为交感靶细胞脱敏能力的开始提供了一个时间信号，但细胞学习如何脱敏并非绝对需要神经支配。在脱敏开始之前，激动剂诱导致敏，这在肾上腺素能活性个体发育激增期间维持生理反应性方面可能很重要。受损动物中缺乏致敏意味着，在生理功能完全建立之前，早期的先驱突触提供了一个营养信号，使细胞在围产期过渡期增加对刺激的敏感性。
