By Harald H. H. W. Schmidt, Franz B. Hofmann, Johannes-Peter Stasch
After the invention of endogenous NO formation within the overdue '80s and the 1998 Nobel Prize in body structure or medication, many researchers and physicians back took an interest within the NO/sGC interplay and cGMP-dependent signaling. This ebook is an enthusiastic social gathering of cyclic guanosine monophosphate (cGMP) and amply illustrates the significance of this box of technology to sufferers and how during which the sector has advanced. it truly is solely dedicated to this interesting and demanding signaling molecule, addressing all contemporary advances in knowing guanylate cyclase rules, NO/sGC interactions, cGMP effector mechanisms and their pathophysiological and pharmacological implications. specific recognition may also be given to scientific functions of the unconventional cGMP-elevating medicinal drugs that are at the horizon, hence spanning the continuum from uncomplicated technology to sanatorium.
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Extra info for cGMP: Generators, Effectors and Therapeutic Implications
R. A. 1 Activator Binding The binding of both NO and CO to the sGC heme has been extensively studied with standard spectroscopic methods such as electronic absorption, resonance Raman (RR) and electron paramagnetic resonance (EPR) to understand how they activate sGC. sGC is isolated in the reduced unligated state which is characterized by an absorbance maximum at 431 nm. While sGC has the same histidine ligated heme cofactor as found in the globins, it has distinct ligand binding properties. Unlike the globin heme, the sGC heme is stable in the presence of molecular oxygen and is not susceptible to oxidation.
NO-GC1-deficient mice showed an increased sensitivity towards the activator of the membrane-bound GC-A, ANP, which can be interpreted as compensatory counter regulation. An alteration of cGMP-degrading phosphodiesterase content has been suggested to be able to compensate for high or low cGMP-forming activities (Kim et al. 2001, 2007). However, PDE activities measured in the aorta homogenate did not differ between KO and WT, therefore a reduced PDE expression as the underlying mechanism for the increased ANP sensitivity was ruled out.
RR spectroscopy shows that the N-O stretch shifts from 1681 to 1700 cm−1 in the presence of GTP (Tomita et al. 1997), and the EPR spectrum of the FeII -NO complex shifts to a unique signal with either GTP or YC-1 addition (Derbyshire et al. 2008; Makino et al. 2003). This indicates that there are at least two sGC FeII -NO conformations of differing activities, and that the abundance of each conformation is influenced by both substrate and activator binding. This proposal is further supported by NO dissociation experiments which show that the sGC ferrous nitrosyl complex adopts two 5-coordinate conformations that are influenced by the presence of GTP and YC-1; a lower-activity complex which releases NO slowly and a higher-activity complex which releases NO rapidly (Winger et al.