Koesling Doris, Russwurm Michael, Mergia Evanthia, Mullershausen Florian, Friebe Andreas
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät MA N1, Ruhr-Universität Bochum, 44780 Bochum, Germany.
Neurochem Int. 2004 Nov;45(6):813-9. doi: 10.1016/j.neuint.2004.03.011.
By the formation of the second messenger cGMP, NO-sensitive guanylyl cyclase (GC) plays a key role within the NO/cGMP signaling cascade which participates in vascular regulation and neurotransmission. The enzyme contains a prosthetic heme group that acts as the acceptor site for NO. High affinity binding of NO to the heme moiety leads to an up to 200-fold activation of the enzyme. Unexpectedly, NO dissociates with a half-life of a few seconds which appears fast enough to account for the deactivation of the enzyme in biological systems. YC-1 and its analogs act as NO sensitizers and led to the discovery of a novel pharmacologically and conceivably physiologically relevant regulatory principle of the enzyme. The two isoforms of the heterodimeric enzyme (alpha1beta1, alpha2beta1) are known that are functionally indistinguishable. The alpha2beta1-isoform mainly occurs in brain whereas the alpha1beta1-enzyme shows a broader distribution and represents the predominantly expressed form of NO-sensitive GC. Until recently, the enzyme has been thought to occur in the cytosol. However, latest evidence suggests that the alpha2-subunit mediates the membrane association of the alpha2beta1-isoform via interaction with a PDZ domain of the post-synaptic scaffold protein PSD-95. Binding to PSD-95 locates this isoform in close proximity to the NO-generating synthases thereby enabling the NO sensor to respond to locally elevated NO concentrations. In sum, the two known isoforms may stand for the neuronal and vascular form of NO-sensitive GC reflecting a possible association to the neuronal and endothelial NO-synthase, respectively.
通过第二信使环磷酸鸟苷（cGMP）的形成，一氧化氮（NO）敏感的鸟苷酸环化酶（GC）在参与血管调节和神经传递的NO/cGMP信号级联反应中起关键作用。该酶含有一个作为NO受体位点的辅基血红素基团。NO与血红素部分的高亲和力结合导致该酶激活高达200倍。出乎意料的是，NO以几秒的半衰期解离，这似乎足够快，足以解释生物系统中该酶的失活。YC-1及其类似物作为NO敏化剂，导致发现了该酶一种新的药理学及可能的生理学相关调节机制。已知异二聚体酶的两种同工型（α1β1、α2β1）在功能上无法区分。α2β1同工型主要存在于大脑中，而α1β同工型分布更广，是NO敏感GC的主要表达形式。直到最近，人们一直认为该酶存在于细胞质中。然而，最新证据表明，α2亚基通过与突触后支架蛋白PSD-95的PDZ结构域相互作用介导α2β1同工型的膜结合。与PSD-95结合使该同工型位于产生NO的合酶附近，从而使NO传感器能够对局部升高的NO浓度作出反应。总之，两种已知的同工型可能分别代表NO敏感GC的神经元形式和血管形式，反映了它们可能分别与神经元型和内皮型NO合酶相关。
