On the activation of soluble guanylyl cyclase by nitric oxide

AUTOR(ES)

Bellamy, Tomas C.

FONTE

The National Academy of Sciences

RESUMO

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.

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