Isoforms of NO-sensitive guanylyl cyclase
Isoforms of NO-sensitive guanylyl cyclase
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DOI：
10.1023/a:1014252309493
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发表时间：
2002-01-01
影响因子：
4.3
通讯作者：
Koesling, D
中科院分区：
文献类型：
--
作者：
Russwurm, M;Koesling, D
通过cGMP的形成，NO敏感的鸟苷酸环化酶在参与血管调节和神经传递的NO/cGMP信号级联中起关键作用。该酶的血红素组作为NO传感器，NO的结合诱导构象变化，导致酶的激活高达200倍。几秒钟的NO的意外快速解离半衰期足够快，足以解释生物系统中酶的失活。YC-1及其类似物作为NO增敏剂，揭示了该酶的一种新的、可想象的生理学相关的调节原理，已知异源二聚体鸟苷酸环化酶的两种存在的同种型（α（1）β（1），α（2）β（1））在功能上是不可区分的。到目前为止，NO敏感的鸟苷酸环化酶一直被认为是一种可溶性酶。然而，最近关于α 2 β 1亚型与突触后支架蛋白PSD-95的PDZ结构域相互作用的证据表明，α 2亚基指导这种亚型的膜结合。与PSD-95的相互作用将α（2）β（1）同种型定位在非常接近于产生NO的NO合酶的位置，从而使NO传感器能够响应局部升高的NO浓度。
By the formation of cGMP the NO-sensitive guanylyl cyclase plays a key role within the NO/cGMP signaling cascade involved in vascular regulation and neurotransmission. The prosthetic heme group of the enzyme acts as the NO sensor, and binding of NO induces conformational changes leading to an up to 200-fold activation of the enzyme. The unexpected fast dissociation half-life of NO of a few seconds is fast enough to account for the deactivation of the enzyme in biological systems. YC-1 and its analogues acting as NO sensitizers uncovered a new pharmacologically and conceivably physiologically relevant regulatory principle of the enzyme.Two existing isoforms of the heterodimeric guanylyl cyclase (alpha(1)beta(1), alpha(2)beta(1)) are known that are functionally indistinguishable. Up to now, the NO-sensitive guanylyl cyclase has been considered as a soluble enzyme. However, recent evidence about the alpha(2)beta(1) isoform interacting with a PDZ domain of the postsynaptic scaffold protein PSD-95 suggests that the alpha(2) subunit directs a membrane association of this isoform. The interaction with PSD-95 locates the alpha(2)beta(1) isoform in close proximity to the NO-generating NO synthase thereby enabling the NO sensor to respond to locally raised NO concentrations.