Diazepam and rolipram differentially inhibit cyclic AMP-specific phosphodiesterases PDE4A1 and PDE4B3 in the mouse
Diazepam and rolipram differentially inhibit cyclic AMP-specific phosphodiesterases PDE4A1 and PDE4B3 in the mouse
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DOI：
10.1016/s0167-4781(01)00164-6
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发表时间：
2001-03-19
期刊：
影响因子：
--
通讯作者：
Pho, V
中科院分区：
文献类型：
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作者：
Cherry, JA;Thompson, BE;Pho, V
环 AMP 被至少八类环核苷酸磷酸二酯酶 (PDE) 的成员水解。尽管有报道称，哺乳动物组织中的环 AMP PDE 活性可以被苯二氮卓类药物抑制，但尚未最终证明环 AMP 特异性、咯利普兰可抑制的 PDE (PDE4) 类成员是这些药物的靶标。此外，尚未对小鼠中表达的 PDE4 进行表征。为了解决这些问题，我们从小鼠大脑文库中分离出了代表 PDE4A1 和 PDE4B3 同源物的两个 cDNA。在人胚肾 (HEK) 293 细胞中瞬时转染后，小鼠 PDE 以低 K-m 水解环 AMP，并被咯利普兰抑制：两者都是其他哺乳动物 PDE4 酶的典型特性。此外。我们发现地西泮抑制小鼠 PDE4 亚型的环 AMP 水解。有趣的是，PDE4B 对咯利普兰和地西泮的抑制作用明显比 PDE4A 亚型更敏感。这是重组表达的 PDE4 受到地西泮抑制的首次证明，并且应该有助于未来对抑郁和焦虑小鼠模型的研究。 (C) 2001 Elsevier Science B.V. 保留所有权利。
Cyclic AMP is hydrolyzed by members of at least eight classes of cyclic nucleotide phosphodiesterases (PDEs). Although it has been reported that cyclic AMP PDE activity in mammalian tissues can be inhibited by benzodiazepines, it has not been conclusively demonstrated that members of the class of cyclic AMP-specific, rolipram-inhibitable PDEs (PDE4s) are targets for these drugs. Moreover, no PDE4s expressed in mice have been characterized. To address these issues, we isolated two cDNAs representing homologues of PDE4A1 and PDE4B3 from a mouse brain library. After transient transfection in human embryonic kidney (HEK) 293 cells, the mouse PDEs hydrolyzed cyclic AMP with a low K-m and were inhibited by rolipram: both are properties typical of other mammalian PDE4 enzymes. In addition. we found that diazepam inhibited cyclic AMP hydrolysis by the mouse PDE4 subtypes. Interestingly, PDE4B was significantly more sensitive to inhibition by both rolipram and diazepam than the PDE4A subtype. This is the first demonstration that recombinantly expressed PDE4s are inhibited by diazepam, and should facilitate future studies with mouse models of depression and anxiety. (C) 2001 Elsevier Science B.V. All rights reserved.