环腺苷酸依赖蛋白激酶激活剂和抑制剂对清醒大鼠体内罗利普兰与磷酸二酯酶 4 结合的影响。
Effects of cAMP-dependent protein kinase activator and inhibitor on in vivo rolipram binding to phosphodiesterase 4 in conscious rats.
机构信息
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
出版信息
Synapse. 2010 Feb;64(2):172-6. doi: 10.1002/syn.20728.
Abstract
Rolipram is a selective inhibitor of phosphodiesterase-4 (PDE4), and positron emission tomography (PET) using [(11)C]rolipram can monitor the in vivo activity of this enzyme that is part of the cAMP second messenger cascade. cAMP-dependent protein kinase (PKA) phosphorylates PDE4 and increases both enzyme activity and affinity for rolipram. In the present PET study, we examined effects of PKA modulators in conscious rats on the binding of (11)C-rolipram in comparison to the much less active enantiomer (11)C-rolipram. Unilateral injection of a PKA activator (dibutyryl-cAMP) and a PKA inhibitor (Rp-adenosine-3',5'-cyclic monophosphorothioate) into the striatum significantly increased and decreased, respectively, the binding of (11)C-rolipram. These effects were not caused by changes in blood flow or delivery of radioligand to brain, since these agents had no effect on the binding of (11)C-rolipram binding. These results support the value of measuring in vivo (11)C-rolipram binding in brain to assess responses to physiological or pharmacological challenges to the cAMP second messenger system.
摘要
罗利普兰是磷酸二酯酶 4（PDE4）的选择性抑制剂，正电子发射断层扫描（PET）使用[（11）C]罗利普兰可以监测这种酶的体内活性，该酶是 cAMP 第二信使级联的一部分。cAMP 依赖性蛋白激酶（PKA）磷酸化 PDE4，增加酶活性和罗利普兰的亲和力。在本 PET 研究中，我们研究了在清醒大鼠中 PKA 调节剂对[（11）C]（R）-罗利普兰结合的影响，与活性低得多的对映异构体[（11）C]（S）-罗利普兰相比。将 PKA 激活剂（二丁酰环 AMP）和 PKA 抑制剂（Rp-腺苷-3'，5'-环单磷酸硫代酯）单侧注射到纹状体中，分别显著增加和减少[（11）C]（R）-罗利普兰的结合。这些影响不是由于血流变化或放射性配体向大脑的输送引起的，因为这些药物对[（11）C]（S）-罗利普兰结合没有影响。这些结果支持测量体内[（11）C]（R）-罗利普兰结合以评估对 cAMP 第二信使系统的生理或药理挑战的反应的价值。
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