DOPAMINE RECEPTOR MODULATION OF CHROMAFFIN CELL FUNCTION

多巴胺受体对嗜铬细胞功能的调节

基本信息

批准号：
3238994
负责人：
ALLAN S SCHNEIDER
金额：
$ 17.13万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-09-01 至 1992-08-31
项目状态：
已结题

项目摘要

The long term goals of this project are to elucidate the role of peripheral dopamine receptors on adrenal chromaffin cells and the mechanisms by which they alter neurotransmitter release. Although dopamine containing cells (SIF cells) are known to be present in sympathetic ganglia, the site of action and role of dopamine in ganglionic function remains obscure. Adrenal chromaffin cells resemble postganglionic, sympathetic neurons in their synthesis, storage and release of catecholamines. It has recently been reported that dopamine receptor agonists inhibit adrenal catecholamine release. We have obtained preliminary evidence for the presence of D2 dopamine receptors on adrenal chromaffin cells, their interaction with GTP binding proteins, and for their inhibition of calcium channels and catecholamine release. We plan to characterize the dopamine receptors on chromaffin cells by radioligand binding techniques, using 3H-N- methylspiperone, a D2 dopamine receptor antagonist, and 3H-N- propylapomorphine, a D2 receptor agonist. The role of dopamine receptors in adrenal medullary function will be determined by measuring the effects of dopaminergic ligands on calcium translocation, cytosolic calcium levels and catecholamine release. The possible role of GTP-binding proteins in the receptor transduction mechanism will be examined by determining the effects of pertussis toxin and cholera toxin and of guanyl nucleotide derivatives on radioligand binding, calcium movements and catecholamine release. In a general sense it is anticipated that new insights into the function of peripheral dopamine receptors and their mechanisms of modulating neurohormone release will result from this project. The specific role of D2 dopamine receptors in regulating adrenal chromaffin cell calcium movements and catecholamine secretion should be clarified. An improved understanding of the pharmacology and cellular regulation of catecholamine release will be relevant to the management of the adrenal medullary tumor, pheochromocytoma. Since adrenaline release is central to the neurochemistry of the acute stress response, there will also be direct relevance to the associated effects on cardiovascular and pulmonary function and hypertension.

该项目的长期目标是阐明肾上腺嗜铬细胞上的外周多巴胺受体它们改变神经递质释放的机制。尽管已知含有多巴胺的细胞（SIF 细胞）存在于交感神经节中，是其作用和作用的部位多巴胺在神经节功能中的作用仍不清楚。肾上腺嗜铬细胞类似于节后交感神经元它们合成、储存和释放儿茶酚胺。它有最近有报道称多巴胺受体激动剂可抑制肾上腺儿茶酚胺释放。我们已初步获得肾上腺上存在 D2 多巴胺受体的证据嗜铬细胞，它们与 GTP 结合蛋白的相互作用，以及抑制钙通道和儿茶酚胺发布。我们计划表征多巴胺受体通过放射性配体结合技术，使用 3H-N- 嗜铬细胞甲基螺哌隆，一种 D2 多巴胺受体拮抗剂，和 3H-N- 丙基阿扑吗啡，一种 D2 受体激动剂。多巴胺的作用肾上腺髓质功能中的受体将由以下因素决定测量多巴胺能配体对钙的影响易位、胞质钙水平和儿茶酚胺释放。 GTP 结合蛋白在受体中的可能作用将通过确定百日咳毒素和霍乱毒素以及鸟苷的影响放射性配体结合、钙移动的核苷酸衍生物和儿茶酚胺释放。一般意义上是预期的对外周多巴胺功能的新见解受体及其调节神经激素的机制发布将由该项目产生。 D2的具体作用多巴胺受体调节肾上腺嗜铬细胞钙应明确运动和儿茶酚胺分泌。一个增进对药理学和细胞的了解儿茶酚胺释放的调节将与肾上腺髓质肿瘤、嗜铬细胞瘤的治疗。由于肾上腺素的释放是神经化学的核心急性应激反应，也与对心血管和肺功能的相关影响高血压。