Cloning of guanylyl cyclase isoforms.
The cloning of particulate and soluble guanylyl cyclases is summarized in Table I. With respect to transmembrane signal transduction systems, guanylyl and adenylyl cyclases can be grouped together with some protein tyrosine kinases and protein tyrosine phosphatases to form a diverse protein family with various structural and functional similarities (Garbers, 1989, 1991, 1992; Koesling et al., 1991; Chinkers and Garbers, 1991; Fig. 1). Particulate guanylyl cyclase contains a single transmembrane domain, and the peptide-binding portion (ligand receptor) is on the exterior surface and the catalytic region on the interior, similar to the protein tyrosine kinase/receptor and the protein tyrosine phosphatase/receptor families (Yarden et al., 1986; Charbonneau et al., 1988; Tonks et al., 1988). Protein tyrosine kinases and phosphatases are also activated by ligand binding to the extracellular domain, which in turn results in phosphorylation or dephosphorylation. On the other hand, soluble guanylyl cyclase exists as a heterodimer with two putative catalytic domains, and both subunits are essential for enzyme activity and activation by nitric oxide. It is thus particularly interesting that adenylyl cyclase also contains two catalytic domains, which are both necessary for catalytic activity (Tang et al., 1991). It is possible that particulate guanylyl cyclase may also dimerize on hormonal stimulation and two catalytic domains from two monomers form a functional catalytic center capable of forming cyclic GMP. The catalytic core of GC-A expressed in bacteria was shown to form a homodimer with positively cooperative kinetics (Thorpe et al., 1991). The physiological significance of the existence of multiple forms of soluble guanylyl cyclase subunits remains unclear. Future studies should reveal the differences in tissue distribution and activation by nitrovasodilators in various heterodimers of soluble guanylyl cyclase.
Nakane
M
M
Pharmaceutical Products Division Abbott Laboratories, Abbott Park, Illinois 60064.
Murad
F
F
D000818:Animals; D003001:Cloning, Molecular; D006162:Guanylate Cyclase / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000737:chemistry
D007527:Isoenzymes; D006162:Guanylate Cyclase