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ABSTRACT-ATP/dithiothreitol (DTT)-stimulated guanylate cyclase (GC) in lung membrane was stimulated 18-fold by ATP and DTT, and both its activity and atrial natriuretic peptide (ANP)-stimulated GC activity were observed to be additive. ATP /DTT-stimulated GC was solubilized by octyl glucoside (OG) to examine the mechanism of ATP /DTT-stimulation. GC in OG-extracts was stimulated maximally 2.5-fold by both ATP, ATPgS or AMPPNP, and DTT. Preincubation of OG-extracts at 10°C with AMPPNP and DTT (1st-preincubation) converted GC to an insensitive state to stimulation by both ATP and DTT, and this conversion was partly inhibited by a protein phosphatase-1 inhibitor (10 -1000 nM okadaic acid). On the other hand, ANP-stimulated GC was not converted to an insensitive state to ANP /ATP-stimulation by the 1st-preincubation. Subsequent preincubation of OG-extracts at 10°C with both DTT and, ATP or ATPgS but not AMPPNP converted GC to a state sensitive to ATP /DTT-stimulation, and this conversion was partly inhibited by inhibitors of Ca 2+ /calmodulin-dependent protein kinase II . In contrast, the preincubation with KN-62 and KN-93 had no effect on ANP-stimulated GC activity. The results suggested that phosphorylation was involved in the regulation of ATP /DTT-stimulated GC sensitivity to ATP /DTTstimulation and that ATP /DTT-stimulated GC activity was likely to be a different type from ANP-stimulated GC activity.

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