CHARACTERIZATION OF THE MAST CELL ANDENOSINE RECEPTOR

缺氧肺组织和IgE刺激的肺组织释放腺苷， 肥大细胞 吸入腺苷引起支气管收缩， 哮喘受试者，和外源性腺苷显着增强 肥大细胞颗粒相关介质的释放。 这 介体释放增加可能与 腺苷诱导肥大细胞环磷酸腺苷含量增加，但 肥大细胞腺苷受体不符合任何 特异性腺苷受体亚型及其作用机制 腺苷在肥大细胞分泌中的作用不确定。 细胞表面 激素受体通常与特异性核苷酸结合 随后激活腺苷酸催化单位的蛋白质 环化酶或其他生物化学过程。 机制是否 腺苷对肥大细胞的作用依赖于N蛋白 偶联和涉及何种类型的N蛋白还不清楚。 本文提出的研究目的是检查桅杆 细胞腺苷受体，与N蛋白的相互作用， 功能要求，如果有的话，连接到环AMP。 这些问题将通过使用代理来解决， 选择性地激活或阻断受体的某些成分- N蛋白-催化单位系统，如霍乱毒素，毛喉素， 或佛波醇酯。 在考虑了耦合的性质之后， 腺苷受体的环腺苷酸，腺苷的影响， 磷酸肌醇代谢、钙动员和蛋白质 将探索激酶活化。 腺苷受体的药理学调节 将被审查。 氨茶碱能够上调 已经描述了肥大细胞腺苷受体， 腺苷类似物NECA可以使肥大细胞受体对腺苷酸的敏感性降低， 腺苷的后续作用。 皮质类固醇可以逆转或 抑制β-肾上腺素能受体的脱敏， 细胞类型，但它们对腺苷受体的作用还没有被证实。 研究了 改变腺苷代谢的药物，如5-脱氧- 5-腺苷激酶抑制剂碘结核菌素也将 研究它们对腺苷受体表达的影响。 在 总的来说，拟议的项目旨在扩大 了解腺苷受体在肥大细胞中的重要性 细胞生物化学，它们与N蛋白的相互作用及其 药理调节 腺苷是一种支气管收缩剂 和速发型超敏反应的增效剂， 关于其在肥大细胞功能中作用的信息应该有助于 用于治疗哮喘的药剂的开发， 过敏性疾病

Adenosine is released by hypoxic lung tissue and by IgE-stimulated mast cells. Inhaled adenosine induces bronchoconstriction in asthmatic subjects, and exogenous adenosine markedly potentiates the release of mast cell granule-associated mediators. This mediator release augmentation may be associated with an adenosine-induced increase in mast cell cyclic AMP content, but mast cell adenosine receptors do not fit the criteria for any specific adenosine receptor subtype, and the mechanism of action of adenosine in mast cell secretion in uncertain. Cell surface hormone receptors often interact with specific nucleotide binding proteins that subsequently activate a catalytic unit of adenylate cyclase or other biochemical processes. Whether the mechanism of action of adenosine on mast cells is dependent on N protein coupling and what type of N protein is involved are as yet unclear. The purpose of the studies proposed herein is to examine the mast cell adenosine receptor, its interactions with N proteins, and its functional requirement, if any, for a linkage to cyclic AMP. These questions will be addressed by utilizing agents that selectively activate or block certain components of the receptor - N protein - catalytic unit system, such as cholera toxin, forskolin, or phorbol esters. After considering the nature of the coupling of adenosine receptors to cyclic AMP, the effects of adenosine on inositol phosphate metabolism, calcium mobilization, and protein kinase activation will be explored. The regulation of adenosine receptors by pharmacologic agents will be examined. The ability of aminophylline to up-regulate mast cell adenosine receptors has been described, and the adenosine analog NECA can desensitize mast cell receptors to the subsequent actions of adenosine. Corticosteroids can reverse or inhibit the desensitization of beta-adrenergic receptors in some cell types, but their action on adenosine receptors has not been studied. Agents that alter adenosine metabolism such as 5-deoxy- 5-iodotubericidin an adenosine kinase inhibitor, will also be studied as to their effects on adenosine receptor expression. In general, the proposed project is intended to broaden the understanding of the importance of adenosine receptors in mast cell biochemistry, their interactions with N proteins and their pharmacologic regulation. As adenosine is a bronchoconstrictor and a potentiator of immediate hypersensitivity reactions, information regarding its role in mast cell function should aid in the development of agents useful in the treatment of asthma and allergic diseases.