Background
ATP was first shown to enhance the activity of natriuretic peptide (NP)-stimulated guanylyl cyclase (GC)-A in 1987 [1]. Later, NP-stimulation of GC-A and GC-B was reported to be dependent on ATP and a model was proposed where ATP binding to the kinase homology domain elevates maximal velocity of these enzymes [2]. Beginning in 1992, we demonstrated that GC-A and GC-B are phosphorylated and that phosphorylation is required for NP-stimulation [3–6]. Subsequently, ATP was shown to increase the phosphorylation and activity of GC-A in vitro, which explained why ATP is required for their activation [7]. Later, we demonstrated that ATP is not required for NP-dependent activation of GC-A and GC-B if phosphatase inhibitors are included in the assay and substrate levels are high [8]. Surprisingly, we found that ATP dramatically reduced the Michaelis constants (Kms) for GC-A and GC-B but had no effect on their maximal velocities [9].