Interactions between cyclic AMP and calcium signalling pathways in airway smooth muscle cells.

气道平滑肌细胞中环磷酸腺苷和钙信号通路之间的相互作用。

• 批准号: BB/I015574/1
• 金额: $ 11.71万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI015574%2F1
• 关键词: Interactions; between; cyclic; AMP; calcium

Ca2+ and cAMP are delivered to cells as spatially organised signals and reciprocal interactions between them are widespread. In bronchial airways, for example, Ca2+ is the primary control of contraction, via activation of myosin light chain kinase, while receptors that evoke cAMP formation cause relaxation. Both pathways are targets of drugs used to treat asthma and chronic obstructive pulmonary disease (COPD), with agonists of beta2-receptors and antagonists of M3 muscarinic receptors in widespread clinical use. In combination therapy, these drugs act at least additively and perhaps synergistically,but the nature of the interactions is undefined. In human bronchial airway smooth muscle cells (BASMC), cAMP attenuates Ca2+ signals and the Ca2+-sensitivity of the contractile apparatus; and Ca2+ attenuates cAMP signalling. The mechanisms underlying these physiologically and clinically important interactions are unresolved. Hitherto interactions between M3 and beta2 receptors have relied on heterologous expression in cell lines, but they need to be explored in native human tissues that retain an appropriate cohort of signalling proteins. Novartis is developing combination therapies for COPD, but there is presently no human pre-clinical model for assessment of their efficacy, and limited knowledge from which to identify possible drug targets downstream of receptors. Human bronchial airway smooth muscle cells (BASMC) in culture largely retain their native phenotype for up to 10 passages, but transfection is required to maintain normal levels of M3 receptors. These cells currently provide the best model for signalling analyses in BASMC. Our aims are to identify sites of interaction between cAMP and Ca2+ in human BASMC stimulated with agonists of beta2 and M3 receptors.

Ca 2+和cAMP作为空间组织的信号被递送到细胞，并且它们之间的相互作用是广泛的。例如，在支气管气道中，Ca 2+通过激活肌球蛋白轻链激酶是收缩的主要控制，而引起cAMP形成的受体引起舒张。这两种途径都是用于治疗哮喘和慢性阻塞性肺病（COPD）的药物的靶点，β 2受体激动剂和M3毒蕈碱受体拮抗剂在临床上广泛使用。在联合治疗中，这些药物至少是相加的，也许是协同的，但相互作用的性质是不确定的。在人支气管气道平滑肌细胞（BASMC）中，cAMP减弱Ca 2+信号和收缩器官的Ca 2+敏感性;并且Ca 2+减弱cAMP信号传导。这些生理和临床上重要的相互作用的机制尚未解决。M3和β 2受体之间的histoprotein相互作用依赖于细胞系中的异源表达，但它们需要在保留适当的信号蛋白组群的天然人体组织中进行探索。诺华公司正在开发COPD的联合疗法，但目前还没有用于评估其疗效的人类临床前模型，并且用于识别受体下游可能的药物靶点的知识有限。培养的人支气管气道平滑肌细胞（BASMC）在很大程度上保留了其天然表型长达10代，但需要转染以维持M3受体的正常水平。这些细胞目前为BASMC中的信号传导分析提供了最佳模型。我们的目的是确定在人BASMC与β 2和M3受体激动剂刺激cAMP和Ca 2+之间的相互作用的网站。