Dessauer Carmen W, Watts Val J, Ostrom Rennolds S, Conti Marco, Dove Stefan, Seifert Roland
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, Texas (C.W.D.); Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (V.J.W.); Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California (R.S.O.); Center for Reproductive Sciences, University of California San Francisco, San Francisco, California (M.C.); Institute of Pharmacy, University of Regensburg, Regensburg, Germany (S.D.); and Institute of Pharmacology, Hannover Medical School, Hannover, Germany (R.S.)
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, Texas (C.W.D.); Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (V.J.W.); Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California (R.S.O.); Center for Reproductive Sciences, University of California San Francisco, San Francisco, California (M.C.); Institute of Pharmacy, University of Regensburg, Regensburg, Germany (S.D.); and Institute of Pharmacology, Hannover Medical School, Hannover, Germany (R.S.).
Pharmacol Rev. 2017 Apr;69(2):93-139. doi: 10.1124/pr.116.013078.
Adenylyl cyclases (ACs) generate the second messenger cAMP from ATP. Mammalian cells express nine transmembrane AC (mAC) isoforms (AC1-9) and a soluble AC (sAC, also referred to as AC10). This review will largely focus on mACs. mACs are activated by the G-protein G and regulated by multiple mechanisms. mACs are differentially expressed in tissues and regulate numerous and diverse cell functions. mACs localize in distinct membrane compartments and form signaling complexes. sAC is activated by bicarbonate with physiologic roles first described in testis. Crystal structures of the catalytic core of a hybrid mAC and sAC are available. These structures provide detailed insights into the catalytic mechanism and constitute the basis for the development of isoform-selective activators and inhibitors. Although potent competitive and noncompetitive mAC inhibitors are available, it is challenging to obtain compounds with high isoform selectivity due to the conservation of the catalytic core. Accordingly, caution must be exerted with the interpretation of intact-cell studies. The development of isoform-selective activators, the plant diterpene forskolin being the starting compound, has been equally challenging. There is no known endogenous ligand for the forskolin binding site. Recently, development of selective sAC inhibitors was reported. An emerging field is the association of AC gene polymorphisms with human diseases. For example, mutations in the AC5 gene () cause hyperkinetic extrapyramidal motor disorders. Overall, in contrast to the guanylyl cyclase field, our understanding of the (patho)physiology of AC isoforms and the development of clinically useful drugs targeting ACs is still in its infancy.
腺苷酸环化酶（ACs）可利用ATP生成第二信使环磷酸腺苷（cAMP）。哺乳动物细胞表达9种跨膜AC（mAC）同工型（AC1 - 9）和1种可溶性AC（sAC，也称为AC10）。本综述将主要聚焦于mACs。mACs由G蛋白G激活，并受多种机制调控。mACs在组织中差异表达，调节众多不同的细胞功能。mACs定位于不同的膜区室并形成信号复合物。sAC由碳酸氢盐激活，其生理作用最初在睾丸中被描述。一种杂交mAC和sAC催化核心的晶体结构已可得。这些结构为催化机制提供了详细见解，并构成了开发同工型选择性激活剂和抑制剂的基础。尽管已有强效的竞争性和非竞争性mAC抑制剂，但由于催化核心的保守性，获得具有高同工型选择性的化合物具有挑战性。因此，在解释完整细胞研究时必须谨慎。以植物二萜福斯可林为起始化合物开发同工型选择性激活剂同样具有挑战性。福斯可林结合位点尚无已知的内源性配体。最近，有报道称开发出了选择性sAC抑制剂。一个新兴领域是AC基因多态性与人类疾病的关联。例如，AC5基因（）的突变会导致运动过度的锥体外系运动障碍。总体而言，与鸟苷酸环化酶领域相比，我们对AC同工型的（病理）生理学以及针对ACs的临床有用药物的开发仍处于起步阶段。
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