Neves-Zaph Susana R
Departments of Pharmacology and Systems Therapeutics, Friedman Brain Institute, System Biology Center New York, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1215, New York, NY, 10029, USA.
Adv Neurobiol. 2017;17:3-14. doi: 10.1007/978-3-319-58811-7_1.
A large number of neuromodulators activate G-protein coupled receptors (GPCRs) and mediate their cellular actions via the regulation of intracellular cAMP, the small highly diffusible second messenger. In fact, in the same neuron several different GPCRs can regulate cAMP with seemingly identical timecourses that give rise to distinct signaling outcomes, suggesting that cAMP does not have equivalent access to all its downstream effectors and may exist within defined intracellular pools or domains. cAMP compartmentalization is the process that allows the neuron to differentially interpret these various intracellular cAMP signals into cellular response. The molecular mechanisms that give rise to cAMP compartmentalization are not fully understood, but it is thought that phosphodiesterases (PDEs), the enzymes that degrade cAMP, significantly contribute to this process. PDEs, as the sole mechanism of signal termination for cAMP, hold great promise as therapeutic targets for pathologies that are due to the dysregulation of intracellular cAMP signaling. Due to their diverse catalytic activity, regulation and localization each PDE subtype expressed in a given neuron may have a distinct role on downstream signaling.
大量神经调质激活G蛋白偶联受体（GPCRs），并通过调节细胞内cAMP（一种高度可扩散的小第二信使）来介导其细胞作用。事实上，在同一神经元中，几种不同的GPCRs可以以看似相同的时间进程调节cAMP，从而产生不同的信号转导结果，这表明cAMP并非能同等地作用于其所有下游效应器，可能存在于特定的细胞内池或区域中。cAMP区室化是指神经元将这些不同的细胞内cAMP信号差异解读为细胞反应的过程。导致cAMP区室化的分子机制尚未完全明确，但人们认为磷酸二酯酶（PDEs），即降解cAMP的酶，在这一过程中发挥了重要作用。PDEs作为cAMP信号终止的唯一机制，有望成为治疗因细胞内cAMP信号失调所致疾病的靶点。由于其多样的催化活性、调节方式和定位，给定神经元中表达的每种PDE亚型可能对下游信号转导具有不同的作用。
