Nitric oxide-sensitive guanylyl cyclase: structure and regulation

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 bi...

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Bibliographic Details
Published in:Neurochemistry International 2004-11, Vol.45 (6), p.813-819
Main Authors: Koesling, Doris, Russwurm, Michael, Mergia, Evanthia, Mullershausen, Florian, Friebe, Andreas
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
cGMP
Enzyme Activation - physiology
Fundamental and applied biological sciences. Psychology
Guanylate Cyclase
Humans
Isoenzymes - metabolism
Isoenzymes - physiology
Nitric oxide
Nitric Oxide - physiology
NO-sensitive guanylyl cyclase
Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear - chemistry
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Cytoplasmic and Nuclear - physiology
Soluble Guanylyl Cyclase
Tissue Distribution
Vertebrates: nervous system and sense organs
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Summary: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 (α 1β 1, α 2β 1) are known that are functionally indistinguishable. The α 2β 1-isoform mainly occurs in brain whereas the α 1β 1-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 α 2-subunit mediates the membrane association of the α 2β 1-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.
ISSN:0197-0186
1872-9754
DOI:10.1016/j.neuint.2004.03.011