The α2β1 isoform of guanylyl cyclase mediates plasma membrane localized nitric oxide signalling
The α2β1 isoform of guanylyl cyclase mediates plasma membrane localized nitric oxide signalling
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DOI：
10.1016/j.cellsig.2007.06.017
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发表时间：
2007-10-01
影响因子：
4.8
通讯作者：
Evans, Thomas J.
中科院分区：
文献类型：
--
作者：
Bellingham, Michelle;Evans, Thomas J.
一氧化氮（NO）是丰富的生物过程的介质，在许多情况下，通过酶一氧化氮敏感的guanyyl环化酶产生cGMP。利钠肽也能提高cGMP，通常具有不同的生物学效应，这就提出了如何实现特异性的问题。在这里，我们发现最近描述的瓜酰环化酶的α (2) β(1)异构体在许多上皮中表达，其中它定位于顶端质膜。我们利用离子通道囊性纤维化跨膜传导调节剂（CFTR）的no依赖性激活来测量α (2) β(1)异构体的功能特性，CFTR是通过cgmp依赖性蛋白激酶的膜结合型异构体磷酸化而发生的。我们发现，NO激活α (2) β(1)环化酶异构体所产生的cGMP是一氧化氮对膜靶作用的一种非常有效的介质，激活CFTR的效率远远高于位于细胞质中的α (2) β(1)环化酶异构体。将瓜酰环化酶的α (2) β(1)异构体靶向到膜上也显著增强了一氧化氮对膜内CFTR的作用。这不是由于在膜位置上的观酰基环化酶的酶活性增加，而是由于膜定位的no依赖的观酰基环化酶产生了局部的cGNIP膜池，这种酶抵抗磷酸二酯酶的降解。由该酶产生的cGNIP对NO的选择性作用是针对膜靶点的，这表明选择性激活或抑制这种α (2) β(1)鸟苷环化酶的药物可能具有独特的药理特性。(c) 2007爱思唯尔公司版权所有。
Nitric oxide (NO) is a mediator of copious biological processes, in many cases through the production of cGMP from the enzyme nitric oxidesensitive guanylyl cyclase. Natriuretic peptides also elevate cGMP, often with distinct biological effects, raising the issue of how specificity is achieved. Here we show that a recently described alpha(2)beta(1) isoform of guarylyl cyclase is expressed in a number of epithelia, where it is localized to the apical plasma membrane. We measured the functional properties of the alpha(2)beta(1) isoform by utilizing the NO-dependent activation of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR), which occurs by phosphorylation via the membrane-bound type II isoform of cGMP-dependent protein kinase. We found that cGMP generated by NO activation of the alpha(2)beta(1) isoform of guanylyl cyclase is an exceptionally efficient mediator of nitric oxide action on membrane targets, activating CFTR far more effectively than the cytoplasmically located alpha(2)beta(1) guanylyl cyclase isoform. Targeting the alpha(2)beta(1) isoform of guarylyl cyclase to the membrane also dramatically enhanced the effects of nitric oxide on CFTR within the membrane. This was not due to increased enzymatic activity of guanylyl cyclase in a membrane location, but to production of a localised membrane pool of cGNIP by membrane-localized NO-dependent guanylyl cyclase that was resistant to degradation by phosphodiesterases. Selective effects of cGNIP produced from this enzyme in response to NO are directed at membrane targets and suggest that drugs selectively activating or inhibiting this alpha(2)beta(1) isoform of guanylyl cyclase may have unique pharmacological properties. (c) 2007 Elsevier Inc. All rights reserved.