Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gα_s so it was long assumed that all ACs are activated by Gα_s-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form prearranged signaling complexes with specific GPCRs that contribute to cAMP signaling compartments. This compartmentation allows for a diversity of cellular and physiological responses by enabling unique signaling events to be triggered by different pools of cAMP. Isoform specific pharmacological activators or inhibitors are lacking for most ACs, making knockdown and overexpression the primary tools for examining the physiological roles of a given isoform. Much progress has been made in understanding the physiological effects mediated through individual transmembrane ACs. GPCR-AC-cAMP signaling pathways play significant roles in regulating functions of every cell and tissue, so understanding each AC isoform's role holds potential for uncovering new approaches for treating a vast array of pathophysiological conditions.

中文翻译：

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哺乳动物跨膜腺苷酸环化酶亚型的生理作用


腺苷酸环化酶 (AC) 催化 ATP 转化为普遍存在的第二信使 cAMP。哺乳动物拥有九种跨膜 AC 亚型，称为 AC1-9，是 G 蛋白偶联受体的主要效应酶。跨膜AC在组织中表现出不同的表达模式，这使得它们具有广泛的生理作用的潜力。细胞表达多种 AC 同工型，这意味着 AC 具有冗余功能。此外，所有跨膜 AC 均由 Gα _s激活，因此长期以来一直假设所有 AC 均由 Gα _s偶联的 GPCR 激活。 AC 异构体​​分配到质膜的不同微域，并与特定的 GPCR 形成预先排列的信号复合物，从而形成 cAMP 信号传导区室。这种划分通过不同的 cAMP 池触发独特的信号事件，从而实现多样化的细胞和生理反应。大多数 AC 缺乏同种型特异性药理激活剂或抑制剂，这使得敲低和过度表达成为检查给定同种型生理作用的主要工具。在理解个体跨膜 AC 介导的生理效应方面已经取得了很大进展。 GPCR-AC-cAMP 信号通路在调节每个细胞和组织的功能中发挥着重要作用，因此了解每种 AC 亚型的作用有可能发现治疗多种病理生理状况的新方法。