Guanylate Cyclase, a Cell Surface Receptor

D L Garbers

doi:10.1016/s0021-9258(18)60495-8

Abstract

Guanylate cyclase appears to represent a central member of a diverse family of proteins involved in cell signaling mechanisms including the protein kinases, a low Mr ANP receptor, and possibly adenylate cyclase (based on limited sequence identity with the yeast enzyme). A membrane form of guanylate cyclase represents a new model for cell surface receptors, although such a model was once envisioned for adenylate cyclase (79). In original models for adenylate cyclase, hormone was thought to bind with either the enzyme or with an unknown protein to enhance cyclic AMP production (79). Guanylate cyclase appears to fall into the first adenylate cyclase model where binding of a ligand to an extracellular site on the enzyme transmits a signal to an intracellular catalytic site. The production of cyclic GMP, a second messenger, and of pyrophosphate are then increased. The protein tyrosine kinase family of receptors (80) and possibly another forthcoming family of cell surface receptors containing protein tyrosine phosphatase activity (81-83) contain a single transmembrane domain like guanylate cyclase. Furthermore, the protein tyrosine kinases are activated by ligand binding to the extracellular domain. However, the activation of guanylate cyclase, unlike these cell surface receptors, results in the formation of a low molecular weight second messenger.

Highlights

Acknowledgment-I would like to thank Dr Joel G
The phosphorylation state of guanylate cyclase dic- Guanylatecyclase appears to represent a central memberof a tates whether or not multiple moleculesof guanylate cyclaseinteract diversefamilyof proteins involved in cell signaliig mechanisms and/or whether the single chain polypeptide contains multiple inter- includingthe protein kinases, alow M
Hardman for his valuable suggestions during the preparation of this manuscript

Summary

The Different Forms of Guanylate Cyclase

Guanylate cyclase is found in various cellular compartments, and the number of different forms still is not resolved. Regulation by Nitrovasodilators-The form of guanylate cyclase that can be regulated by nitrovasodilators, fatty acid oxidation products, and free radicals appears to exist in the cytoplasm. This form of the enzyme likely serves as a receptor for endothelial cell-derived relaxing factor, a substancebelieved by investigators to be nitric oxide [19]. Gerzer et al [22]showed heme to be a prostheticgroup and established the mechanism by which guanylate cyclase is activated by NO and similar molecules These molecules bind to the heme group and, by mechanisms that arestillnot well understood, activate the enzyme. The plasma membrane-associated forms of guanylate cyclase, known to be transmembrane proteins [29],can be regulated by various peptides. In membrane preparations or in detergent-solubilized preparations, the membrane forms of the enzyme characteristically display positive cooperative behavior as a function of the substrate, metalGTP [10, 11, 31]; this distinguishes these forms of the enzyme from those found in the cytoplasm, which exhibit linear kinetics as a function of substrate [10, 11]

Extracellular Peptides ThaItncrease Guanylate Cyclase Activity

Receptors for Peptides That Activate GuanylCatyeclase

Regulation of the Membrane Form of Guanylate Cyclase

Rat brain'

Members of the Guanylate Cyclase Family Based on

Summary