What is the mechanism of action of cGMP?

The primary mechanism of action of cGMP (cyclic guanosine monophosphate) involves the activation of cGMP-dependent protein kinases (PKG), leading to downstream effects such as smooth muscle relaxation.

Here's a breakdown of the mechanism:

1. cGMP Production:

• cGMP is synthesized from GTP (guanosine triphosphate) by the enzyme guanylyl cyclase (GC).
• GC can be activated by various stimuli, including:
  • Nitric oxide (NO): NO activates soluble guanylyl cyclase (sGC), a primary target in smooth muscle.
  • Natriuretic peptides (e.g., ANP, BNP): These peptides activate particulate guanylyl cyclase (pGC), which are transmembrane receptors.

2. Activation of cGMP-Dependent Protein Kinases (PKGs):

• Elevated cGMP levels bind to PKGs. PKGs are serine/threonine kinases.
• cGMP binding causes a conformational change in PKG, activating its kinase activity.

3. Downstream Effects Mediated by PKG:

PKG phosphorylates a variety of target proteins, leading to various physiological effects. The main effect related to the reference is smooth muscle relaxation, which occurs through several mechanisms:

• Reduction of Intracellular Ca²⁺ Concentration:
  • PKG can stimulate Ca²⁺-ATPases in the plasma membrane and sarcoplasmic reticulum, promoting Ca²⁺ efflux and sequestration, respectively. This lowers the cytosolic Ca²⁺ concentration.
  • PKG can inhibit voltage-gated Ca²⁺ channels, reducing Ca²⁺ influx into the cell.
• Decreased Calcium Sensitivity of the Contractile Apparatus:
  • PKG can phosphorylate proteins involved in the regulation of smooth muscle contraction, such as myosin light chain phosphatase (MLCP).
  • Phosphorylation of MLCP increases its activity, leading to dephosphorylation of myosin light chains (MLC). Dephosphorylated MLC reduces the interaction of actin and myosin, resulting in smooth muscle relaxation.
• Potassium Channel Activation: PKG can activate certain potassium channels, leading to hyperpolarization of the smooth muscle cell membrane. Hyperpolarization reduces the likelihood of Ca²⁺ entry, promoting relaxation.
• Inhibition of RhoA/Rho Kinase Pathway: PKG can inhibit the RhoA/Rho kinase pathway, which is involved in Ca²⁺ sensitization. Rho kinase phosphorylates myosin phosphatase targeting subunit 1 (MYPT1), inhibiting MLCP activity and promoting contraction.

In summary, cGMP exerts its effects, particularly smooth muscle relaxation, by activating PKG. PKG then phosphorylates various downstream targets, leading to decreased intracellular Ca²⁺ levels and reduced sensitivity of the contractile machinery to Ca²⁺.