On the Activation of Soluble Guanylyl Cyclase by Nitric Oxide

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-01, Vol.99 (1), p.507-510
• Main Authors: Bellamy, Tomas C., Wood, John, Garthwaite, John
• Format: Article
• Language: English
• Subjects: Agonists; Binding Sites; Biological Sciences; Cells; Classical mechanics; Cyclic GMP - metabolism; Enzymes; Experimental data; Guanylate Cyclase; Heme - chemistry; Humans; Kinetics; Mathematical constants; Modeling; Models, Chemical; Nitric Oxide - metabolism; Oxides; Pharmacology; Physiological regulation; Protein Binding; Protein Conformation; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction; Soluble Guanylyl Cyclase; Studies; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.012368499

Soluble guanylyl cyclase (sGC) is the major cellular receptor for the intercellular messenger nitric oxide (NO) and mediates a wide range of physiological effects through elevation of intracellular cGMP levels. Critical to our understanding of how NO signals are decoded by receptive cells and translated into a useful physiological response is an appreciation of the molecular and kinetic details of the mechanism by which NO activates sGC. It is known that NO binds to a haem prosthetic group on the receptor and triggers a conformational change that increases the catalysis of cGMP synthesis by several hundred-fold. The haem is covalently attached to sGC at His-105 of the β1 subunit, and it was thought previously that activation of sGC by NO occurs in two steps: binding of NO to the haem to form a biliganded state and then rupture of the bond to His-105 triggering an increase in catalytic activity. A recent investigation of the kinetics of sGC activation [Zhao, Y., Brandish, P. E., Ballou, D. P. & Marletta, M. A. (1999) Proc. Natl. Acad. Sci. USA, 96, 14753-14758], however, proposed an additional mechanism by which NO regulates sGC activity, namely, by influencing the rate of cleavage of the His-105 bond. The existence of a second (unidentified) NO-binding site on the enzyme was hypothesized and suggested to be fundamental to cellular NO-signal transduction. Here, we show that it is unnecessary to postulate any such additional mechanism because the results obtained are predicted by the simpler model of sGC activation with a single NO-binding event.