Regulation of the Pathway by Protein Kinase G

The cyclic GMP pathway is regulated at the level of the different enzymes implicated. This regulation is complex and in the case of certain key enzymes is treated in specific pages of this web site (see for example the regulation of nitric oxide synthase or NOS in the page eNOS REGULATION). However, some factors can be considered general regulators of the pathway. This is the case, for example, of calcium and of protein kinase G (PKG).

Calcium

This cation increase the activity of calcium-dependent nitric oxide synthases (NOS-I and NOS-III), a key step in the synthesis of cyclic GMP by soluble guanylyl cyclase. On the other hand, calcium can decrease synthesis of cyclic GMP by inhibiting soluble guanylyl cyclase and increase cyclic GMP degradation by activating a calcium-dependent phosphodiesterase (PDE1).

PKG

Protein kinase G enzyme that phosphorylate several proteins after activation by cyclic GMP, act on different steps of the pathway, altering cyclic GMP synthesis and degradation.

The scheme shown is focused on the hypothetical central role of PKG in the regulation of the pathway. PKG directly stimulates NOS-III (or eNOS), sGC itself and inhibits PDE5 (that selectively degrades cyclic GMP). That is, cyclic GMP, through activation of PKG, can modulate its own synthesis (NOS-III and sGC) and its degradation. On the other hand, PKG can also modulate the intracellular calcium concentration, key ion for the activity of NOS-III (eNOS) and NOS-I (nNOS).

Cytosolic calcium is modulated by PKG through several mechanisms that are not specified for simplicity (besides acting on IRAG -shown in the scheme- and on calcium-ATPase at the endoplasmic reticulum, PKG modulates calcium entry at the plasmatic membrane acting at least on L-type calcium channels, on store-operated calcium entry and on mechanosensitive calcium-permeable channels).