磷酸二酯酶4研究进展

环腺苷酸(cAMP)和环鸟苷酸(cGMP)对于细胞的许多功能有重要作用。磷酸二酯酶(PDEs)催化cAMP和cGMP水解开环分别生成AMP和GMP,这是细胞内降解cAMP和cGMP的唯一途径。PDEs可分为11个家族,其中有8个家族可以水解cAMP,包括能专一性地水解cAMP的PDE家族(如PDE4),和既可水解cAMP又可水解cGMP的PDE家族。PDE4同工酶主要存于在炎症细胞中。PDE4可分为A、B、C、D 4个亚家族,根据其N端的特殊结构,有长、短和超短三种形式。PDE4催化区三维结构的阐明有助于它们功能的研究和相关药物的设计。PDE4通过与其它蛋白如抑制蛋白、A激-酶锚定蛋白(AKAP)以及活化的C激酶1受体(RACK1)等相互作用使cAMP浓度区域化,选择性地调节各种细胞功能。PDE4作为一个治疗靶点,研究其选择性抑制剂具有重要的意义,可以用于治疗由炎症引起的疾病,如哮喘、慢性阻塞性肺疾病(COPD)、阿尔采末病(AD)、帕金森病(PD)和中风等由潜在的炎症引起神经元受损造成的中枢神经系统疾病。

Progress in the study of phosphodiesterases 4

Cyclic AMP(cAMP) and cyclic GMP(cGMP) are of pivotal importance in determining many aspects of cellular function.Cyclic nucleotide phosphodiesterases(PDEs) provide the only route for catalyzing the hydrolysis of cAMP and cGMP into AMP and GMP.In the eleven different PDE families,there are eight PDE families capable of hydrolyzing cAMP,some hydrolyze cAMP exclusively(e.g.PDE4),whereas others hydrolyze cAMP and cGMP.PDE4 is the predominant family in inflammatory cells,and this family can be divided into A,B,C and D subfamilies.Three forms of PDE4-long form,short form and super-short form are found according to their unique N-terminal region.Crystallography studies of the PDE4 catalytic domain provide a framework for the structure-oriented drug design and the functional analysis.PDE4 isoforms determine the compartmentalisation of cAMP by interaction with other proteins such as arrestin,A-kinase anchoring proteins(AKAP) and receptor for activated C kinase 1(RACK1).The selective inhibition of this family generates profound,functional effects and PDE4 family has been used as a therapeutic target for inflammatory diseases,such as asthma,chronic obstructive pulmonary disease(COPD) and CNS diseases in which neuronal damage occurs as consequence of an underlying inflammation,such as Alzheimers disease(AD),stroke and Parkinsons disease(PD).