Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Sci Signal. 2012 Apr 10;5(219):ra29. doi: 10.1126/scisignal.2002299.
The interplay between calcium ion (Ca(2+)) and cyclic adenosine monophosphate (cAMP) signaling underlies crucial aspects of cell homeostasis. The membrane-bound Ca(2+)-regulated adenylyl cyclases (ACs) are pivotal points of this integration. These enzymes display high selectivity for Ca(2+) entry arising from the activation of store-operated Ca(2+) (SOC) channels, and they have been proposed to functionally colocalize with SOC channels to reinforce crosstalk between the two signaling pathways. Using a multidisciplinary approach, we have identified a direct interaction between the amino termini of Ca(2+)-stimulated AC8 and Orai1, the pore component of SOC channels. High-resolution biosensors targeted to the AC8 and Orai1 microdomains revealed that this protein-protein interaction is responsible for coordinating subcellular changes in both Ca(2+) and cAMP. The demonstration that Orai1 functions as an integral component of a highly organized signaling complex to coordinate Ca(2+) and cAMP signals underscores how SOC channels can be recruited to maximize the efficiency of the interplay between these two ubiquitous signaling pathways.
钙离子 (Ca(2+)) 和环腺苷酸 (cAMP) 信号之间的相互作用是细胞内稳态的关键方面。膜结合的 Ca(2+) 调节的腺苷酸环化酶 (ACs) 是这种整合的关键点。这些酶对来自 SOC 通道激活的 Ca(2+) 进入具有高选择性，并且已经提出它们与 SOC 通道在功能上共定位以增强两种信号通路之间的串扰。使用多学科方法，我们已经确定了 Ca(2+) 刺激的 AC8 和 SOC 通道的孔组件 Orai1 的氨基末端之间的直接相互作用。针对 AC8 和 Orai1 微区的高分辨率生物传感器显示，这种蛋白质-蛋白质相互作用负责协调 Ca(2+) 和 cAMP 的亚细胞变化。证明 Orai1 作为高度组织化信号复合物的一个组成部分发挥作用，以协调 Ca(2+) 和 cAMP 信号，强调了 SOC 通道如何被招募以最大化这两种普遍存在的信号通路之间相互作用的效率。
