Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Jan;385(1):5-12. doi: 10.1007/s00210-011-0696-9. Epub 2011 Oct 20.
Adenylyl cyclases are a ubiquitous family of enzymes and are critical regulators of metabolic and cardiovascular function. Multiple isoforms of the enzyme are expressed in a range of tissues. However, for many processes, the adenylyl cyclase isoforms have been thought of as essentially interchangeable, with their impact more dependent on their common actions to increase intracellular cyclic adenosine monophosphate content regardless of the isoform involved. It has long been appreciated that each subfamily of isoforms demonstrate a specific pattern of "upstream" regulation, i.e., specific patterns of ion dependence (e.g., calcium-dependence) and specific patterns of regulation by kinases (protein kinase A (PKA), protein kinase C (PKC), raf). However, more recent studies have suggested that adenylyl cyclase isoform-selective patterns of signaling are a wide-spread phenomenon. The determinants of these selective signaling patterns relate to a number of factors, including: (1) selective coupling of specific adenylyl cyclase isoforms with specific G protein-coupled receptors, (2) localization of specific adenylyl cyclase isoforms in defined structural domains (AKAP complexes, caveolin/lipid rafts), and (3) selective coupling of adenylyl cyclase isoforms with specific downstream signaling cascades important in regulation of cell growth and contractility. The importance of isoform-specific regulation has now been demonstrated both in mouse models as well as in humans. Adenylyl cyclase has not been viewed as a useful target for therapeutic regulation, given the ubiquitous expression of the enzyme and the perceived high risk of off-target effects. Understanding which isoforms of adenylyl cyclase mediate distinct cellular effects would bring new significance to the development of isoform-specific ligands to regulate discrete cellular actions.
腺苷酸环化酶是一个普遍存在的酶家族，是代谢和心血管功能的关键调节剂。该酶的多种同工型在多种组织中表达。然而，对于许多过程，腺苷酸环化酶同工型被认为基本上是可互换的，它们的影响更多地取决于其共同作用来增加细胞内环腺苷酸单磷酸含量，而与涉及的同工型无关。长期以来，人们一直认为每个同工型亚家族都表现出特定的“上游”调节模式，即特定的离子依赖性模式（例如，钙依赖性）和特定的激酶调节模式（蛋白激酶 A（PKA）、蛋白激酶 C（PKC）、raf）。然而，最近的研究表明，腺苷酸环化酶同工型选择性信号转导模式是一种广泛存在的现象。这些选择性信号转导模式的决定因素与许多因素有关，包括：（1）特定的腺苷酸环化酶同工型与特定的 G 蛋白偶联受体的选择性偶联，（2）特定的腺苷酸环化酶同工型在特定结构域（AKAP 复合物、质膜小窝/脂筏）中的定位，以及（3）特定的腺苷酸环化酶同工型与对细胞生长和收缩性调节很重要的特定下游信号级联的选择性偶联。在小鼠模型和人类中都已经证明了同工型特异性调节的重要性。由于酶的普遍表达和认为脱靶效应的高风险，腺苷酸环化酶一直没有被视为治疗调节的有用靶点。了解哪种腺苷酸环化酶同工型介导特定的细胞效应将为开发同工型特异性配体以调节离散的细胞作用带来新的意义。
