Guanylate Cyclase Inhibitors

Guanylyl cyclase (GC) catalyzes the formation of the second messenger cyclic GMP (cGMP) from GTP and exists in both the soluble and particulate fractions. The soluble enzyme can be regulated by free radicals and nitrovasodialators, whereas the particulate enzyme can be regulated by various peptides. cGMP signaling is mediated by cGMP-activated protein kinases, the cGMP-regulated phosphodiesterases and the cGMP-gated ion channels. The action of cGMP is terminated by the action of cGMP-degrading phosphodiesterases. GC is present either as soluble (sGC) or as membrane-bound enzyme linked to a receptor. sGC is activated by another second messenger, nitric oxide (NO). Membrane-bound GC, on the other hand, is activated by hormones. The prosthetic heme group of sGC acts as the NO sensor, and binding of NO induces conformational changes leading to an up to 200-fold activation of the enzyme. The organic nitrates commonly used in the therapy of coronary heart disease exert their effects via stimulation of this enzyme. Two isoforms of the NO-sensitive heterodimeric enzyme have been identified, the ubiquitous α1Β1 isoform and the less broadly distributed α2β1 isoform. These two forms differ in their subcellular distribution.

Membrane-bound GCs are receptor-linked enzymes with one membrane-spanning region. Although all of these GCs share a conserved intracellular catalytic domain, they differ in their extracellular ligand-binding domains and are activated by different peptide hormones. The guanylyl cyclase A (GC-A) isoform acts as the receptor for the natriuretic peptides, ANP and BNP, and hormones that are involved in the regulation of blood pressure as well as in the water and electrolyte household. GC-B is mainly found in the vascular endothelium and is thought to participate in smooth muscle relaxation. It displays the highest affinity for the natriuretic peptide of the C-type (CNP). GC-C is reported to bind the peptide hormone guanylin found in the intestine, where it is involved in salt and water balance. GC-C is stimulated by the heat-stable enterotoxin produced by E. coli.

References:
Friebe, A., and Koesling, D. 2003. Cir. Res. 93, 96.
Denninger, J.W., and Marletta M.A. 1999. Biochim. Biophys. Acta 1411, 334.
Russwurm, M., and Koesling, D. 2002. Mol. Cell Biochem. 230, 159.
Koesling, D., and Friebe, A. 1999. Rev. Physiol. Biochem. Pharmacol. 135, 35.