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New insight into the functioning of nitric oxide-receptive guanylyl cyclase: physiological and pharmacological implications

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Abstract

The cellular counterpart of the “soluble” guanylyl cyclase found in tissue homogenates over 30 years ago is now recognized as the physiological receptor for nitric oxide (NO). The ligand-binding site is a prosthetic haem group that, when occupied by NO, induces a conformational change in the protein that propagates to the catalytic site, triggering conversion of GTP into cGMP. This review focuses on recent research that takes this basic information forward to the beginnings of a quantitative depiction of NO signal transduction, analogous to that achieved for other major transmitters. At its foundation is an explicit enzyme-linked receptor mechanism for NO-activated guanylyl cyclase that replicates all its main properties. In cells, NO signal transduction is subject to additional, activity-dependent modifications, notably through receptor desensitization and changes in the activity of cGMP-hydrolyzing phosphodiesterases. The measurement of these parameters under varying conditions in rat platelets has made it possible to formulate a cellular model of NO-cGMP signaling. The model helps explain cellular responses to NO and their modification by therapeutic agents acting on the guanylyl cyclase or phosphodiesterase limbs of the pathway.

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Acknowledgments

Research in my laboratory is supported by a programme grant from The Wellcome Trust (reference 081512/Z/06/Z). I would also like to acknowledge the important contributions made (in chronological order) by Tomas Bellamy, John Wood, Victoria Wykes, Barry Gibb, Charmaine Griffiths, Elaine Mo, Hemisha Amin, Brijesh Roy, Jeffrey Vernon, and Edward Halvey to the research by our group on NO-activated guanylyl cyclase.

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    John Garthwaite

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Garthwaite, J. New insight into the functioning of nitric oxide-receptive guanylyl cyclase: physiological and pharmacological implications. Mol Cell Biochem 334, 221–232 (2010). https://doi.org/10.1007/s11010-009-0318-8

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