Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxide

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Abstract
Nitric oxide (NO) is a ubiquitous, cell-permeable intercellular messenger1. The current concept assumes that NO diffuses freely through the plasma membrane2 into the cytoplasm of a target cell, where it activates its cytosolic receptor enzyme3, soluble guanylyl cyclase (sGC). Recent evidence, however, suggests that cellular membranes are not only the predominant site of calcium-dependent NO synthesis4, but also the site of its distribution and binding5. Here we extend this concept to NO signalling to show that active sGC is partially associated with the plasma membrane in a state of enhanced NO sensitivity. After cellular activation, sGC further translocates to the membrane fraction in human platelets and associates with the NO-synthase-containing caveolar fraction in rat lung endothelial cells, in a manner that is dependent on the concentration of intracellular calcium. Our data suggest that the entire NO signalling pathway is more spatially confined than previously assumed and that sGC dynamically translocates to the plasma membrane, where it is sensitized to NO.