Plasma Membrane Guanylate Cyclase

Cyclic GMP was discovered in rat urine (Ashman et al., 1963) at almost the same time the remarkable discovery of cyclic AMP was made (Sutherland and Rall, 1960). Mimicking the conceptual framework formulated for the second messenger role of cyclic AMP, cyclic GMP was also proposed to act as a second messenger of certain hormonal signals (reviewed in: Goldberg and Haddox, 1977). Great excitement was generated in the signal transduction field with the “Ying Yang” hypothesis, which predicted that the biological regulation of a cell is governed by the opposing biological activities of cyclic AMP and cyclic GMP (Goldberg and Haddox 1975). However, this and the general concept bearing upon the second messenger role of cyclic GMP in receptor-mediated signal transduction processes became seriously compromised because a) the attempts to demonstrate a hormonally dependent guanylate cyclase failed in every tested system (Goldberg and Haddox, 1977); in contrast, the guanylate cyclase activity was nonspecifically stimulated by a variety of agents such as polyunsaturated fatty acids, peroxides, hydroperoxides, free radicals, ascorbic acid, sodium nitroprusside, and other agents that presumably affected the oxidation-reduction potential of the biochemical reactions (Murad et al., 1979); and b) there was a general consensus that cyclic GMP-dependent protein kinase—at the time the only known effector enzyme of cyclic GMP signal transduction—does not phosphorylate a specific protein (substrate) clearly distinct from that of the cyclic AMP-dependent protein kinase (Gill and McCune, 1979). Despite the fact that the very initial studies had suggested the existence of distinct forms of soluble and particulate guanylate cyclase which could be differentiated from each other by their physical and certain kinetic properties (Kimura and Murad, 1975a, 1975b; Nakazawa et al., 1976; Siegel et al., 1976), the mere fact that guanylate cyclase could be nonspecifically stimulated by non-hormonal agents made these original observations on the independent existence of hormonally dependent guanylate cyclase suspect.