By Harald H. H. W. Schmidt, Franz B. Hofmann, Johannes-Peter Stasch
After the invention of endogenous NO formation within the past due '80s and the 1998 Nobel Prize in body structure or drugs, many researchers and physicians back got interested within the NO/sGC interplay and cGMP-dependent signaling. This ebook is an enthusiastic occasion of cyclic guanosine monophosphate (cGMP) and amply illustrates the significance of this box of technology to sufferers and how within which the sector has developed. it truly is completely dedicated to this intriguing and critical signaling molecule, addressing all fresh advances in knowing guanylate cyclase legislation, NO/sGC interactions, cGMP effector mechanisms and their pathophysiological and pharmacological implications. specific consciousness can be given to medical functions of the unconventional cGMP-elevating medicines that are at the horizon, therefore spanning the continuum from uncomplicated technology to health center.
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Additional info for cGMP: Generators, Effectors and Therapeutic Implications
The discrepancy in gender-dependent hypertension may very well be related to the genetic background of the animals as the NO-GC1 KOs Genetic Mouse Models of the NO Receptor ‘Soluble’ Guanylyl Cyclases 41 are either on a mixed 129/C57BL6 (Mergia et al. 2006) or 129/Swiss or pure 129 background (Buys et al. 2008). When NO-GC1 KO mice were challenged with the NO synthase inhibitor L-NAME, the increase in blood pressure was comparable to that seen in WT mice demonstrating that NO-induced cGMP synthesis, although being greatly reduced, still has an important impact on vascular tone.
EMBO J 26:578–588 Ma X, Sayed N, Baskaran P, Beuve A, van den Akker F (2008) PAS-mediated dimerization of soluble guanylyl cyclase revealed by signal transduction histidine kinase domain crystal structure. J Biol Chem 283:1167–1178 Makino R, Obayashi E, Homma N, Shiro Y, Hori H (2003) YC-1 facilitates release of the proximal His residue in the NO and CO complexes of soluble guanylate cyclase. J Biol Chem 278:11130– 11137 Martin E, Czarnecki K, Jayaraman V, Murad F, Kincaid J (2005) Resonance Raman and infrared spectroscopic studies of high-output forms of human soluble guanylyl cyclase.
A low-activity FeII -NO complex can be formed in the presence of stoichiometric amounts of NO, and based on electronic absorption spectroscopy this species is identical to the highly active enzyme that is formed in the presence of substrate, products, YC-1, or excess NO. Based on these observations two mechanisms of NO activation have been proposed. One proposal is that excess NO activates the ferrous nitrosyl complex by binding to a nonheme site on the protein (Cary et al. 2005). The second proposal involves NO binding to the FeII -NO complex to form a transient dinitrosyl complex, which then converts to a 5-coordinate complex with NO bound in the proximal heme pocket (Russwurm and Koesling 2004) (Fig.
cGMP: Generators, Effectors and Therapeutic Implications by Harald H. H. W. Schmidt, Franz B. Hofmann, Johannes-Peter Stasch