cGMP-PKG signaling pathway

cGMP-PKG signaling pathway

What Is cGMP?

cGMP (cyclic guanosine 3', 5'-monophosphate), a second messenger, is produced due to the catalyzation on the guanosine triphosphate (GTP) by guanylate cyclase (GC). cGMP has three main targets: cGMP-dependent protein kinase or protein kinase G (PKG), cGMP-regulated phosphodiesterase (PDE), and cyclic nucleotide cationic gated channelcyclic guanosine-gated ion channel (CNG). PKG, a universal eukaryotic Ser/Thr kinase, is the most important downstream target of cGMP.

What Is the cGMP-PKG Signaling Pathway?

In the cGMP-PKG signaling pathway, PKG is activated by the second messenger cGMP and then transmits extracellular signals into the cell.

The Function of the cGMP-PKG Signaling Pathway

cGMP-PKG signaling pathway mediates many processes such as the regulation of relaxation and contraction of vascular smooth muscle cells, anti - cardiac hypertrophy, anti-atherosclerosis, and anti-vascular injury/restenosis.

The Process of the cGMP-PKG Signaling Pathway

Nitric oxide (NO) stimulates soluble guanylate cyclase (sGC) to catalyze the intracellular synthesis of cGMP. cGMP activates PKG. Active PKG phosphorylates PLB (phospholamban) on the sarcoplasmic reticulum (SR). Phosphorylated PLB dissociates from Ca2+-ATPase (SERCA-2a) and restores Ca2+-ATPase activity. Activated Ca2+-ATPase transfers Ca2+ from cytoplasm to the sarcoplasmic reticulum, making intracellular Ca2+ level decline. And PKG (PKG-β) catalyzes the phosphorylation of IRAG (IP3 receptor-associated PKG-I substrate), inhibiting the release of Ca2+ mediated by IP3R. These two processes cause Ca2+ to accumulate in the sarcoplasmic reticulum. And then, the accumulated Ca2+ is released into the lower region of the cytoplasmic membrane, triggering spontaneous outward current and activating BK channels. The final result is to realize cardiomyocytes' relaxation.

Or the activation of particulate guanylate cyclase (PGC) by ANP (atrial natriuretic peptide) facilitates the production of cGMP. PKG is subsequently activated by increased cGMP, which phosphorylates protein substrates, causing cellular effects, such as decreased intracellular Ca2+ concentrations in smooth muscle and platelets.

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