The drug efflux transporters ABCB1 and ABCG2 at the blood-brain barrier limit the delivery of drugs into the brain. Strategies to overcome ABCB1/ABCG2 have been largely unsuccessful, which poses a tremendous clinical problem to successfully treat central nervous system (CNS) diseases. Understanding basic transporter biology, including intracellular regulation mechanisms that control these transporters, is critical to solving this clinical problem.

In this comprehensive review, we summarize current knowledge on signaling pathways that regulate ABCB1/ABCG2 at the blood-brain barrier. In Section I, we give a historical overview on blood-brain barrier research and introduce the role that ABCB1 and ABCG2 play in this context. In Section II, we summarize the most important strategies that have been tested to overcome the ABCB1/ABCG2 efflux system at the blood-brain barrier. In Section III, the main component of this review, we provide detailed information on the signaling pathways that have been identified to control ABCB1/ABCG2 at the blood-brain barrier and their potential clinical relevance. This is followed by Section IV, where we explain the clinical implications of ABCB1/ABCG2 regulation in the context of CNS disease. Lastly, in Section V, we conclude by highlighting examples of how transporter regulation could be targeted for therapeutic purposes in the clinic.

血脑屏障处的药物外排转运蛋白 ABCB1 和 ABCG2 限制药物输送到大脑中。克服 ABCB1/ABCG2 的策略基本上不成功，这给成功治疗中枢神经系统 (CNS) 疾病带来了巨大的临床问题。了解基本的转运蛋白生物学，包括控制这些转运蛋白的细胞内调节机制，对于解决这一临床问题至关重要。

在这篇综合综述中，我们总结了目前关于调节血脑屏障 ABCB1/ABCG2 信号通路的知识。在第一节中，我们对血脑屏障研究进行了历史概述，并介绍了 ABCB1 和 ABCG2 在这方面发挥的作用。在第二节中，我们总结了已测试的克服血脑屏障 ABCB1/ABCG2 外排系统的最重要策略。在本次综述的主要组成部分第三节中，我们提供了已确定的控制血脑屏障 ABCB1/ABCG2 的信号通路及其潜在临床相关性的详细信息。接下来是第四节，我们解释了 ABCB1/ABCG2 调节在 CNS 疾病背景下的临床意义。最后，在第五节中，