Regulation of guanylate cyclase activity by atrial natriuretic factor and protein kinase C

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Abstract
The putative ‘second messenger’ of certain atrial natriuretic factor (ANF) signal transductions is cyclic GMP. Recently, we purified a 180-kDa protein, apparently containing both ANF receptor and guanylate cyclase activities, and hypothesized that this is one of the cyclic GMP transmembrane signal transducers. The enzyme is ubiquitous and appears to be conserved. Utilizing the 180-kDa membrane guanylate cyclase, we now show that the 180-kDa guanylate cyclase is regulated in opposing fashions by two receptor signals—ANF stimulating it and protein kinase C inhibiting it. Furthermore, protein kinase C phosphorylates the 180-kDa enzyme. This suggests a novel ‘switch on’ and ‘switch off’ mechanism of the cyclic GMP signal transduction. ‘Switch off’ represents the phosphorylation while ‘switch on’ the dephosphorylation of the enzyme.