negative regulation of cGMP-mediated signaling

Definition

Target type: biologicalprocess

Any process that decreases the rate, frequency or extent of cGMP-mediated signaling. [GOC:BHF, GOC:dph, GOC:tb]

Negative regulation of cGMP-mediated signaling encompasses a diverse array of mechanisms that modulate the cellular responses elicited by cyclic GMP (cGMP). cGMP is a second messenger molecule that plays pivotal roles in a wide range of physiological processes, including smooth muscle relaxation, neurotransmission, and phototransduction. Its actions are mediated by the activation of downstream effectors, primarily protein kinases (PKG) and phosphodiesterases (PDE). Negative regulation of cGMP signaling ensures tight control over these processes, preventing aberrant or excessive signaling.

Key mechanisms involved in the negative regulation of cGMP-mediated signaling include:

1. **cGMP degradation:** PDEs, a family of enzymes, catalyze the hydrolysis of cGMP to 5'-GMP, effectively reducing its intracellular concentration. Different PDE isoforms exhibit distinct substrate specificities and tissue distribution, allowing for fine-tuned regulation of cGMP signaling in various cell types.

2. **Inhibition of guanylate cyclase:** Guanylate cyclases (GCs) are responsible for synthesizing cGMP from GTP. Negative regulation can occur through the inhibition of GC activity. This can be achieved by various mechanisms, including:
* **Ligand binding:** Certain GCs are activated by specific ligands, such as nitric oxide (NO) or atrial natriuretic peptide (ANP). Blocking these ligands or their receptors can prevent GC activation.
* **Phosphorylation:** GCs can be phosphorylated by kinases, leading to their inactivation.
* **Calcium signaling:** Elevated intracellular calcium levels can suppress GC activity.

3. **Regulation of cGMP effector proteins:**
* **PKG inactivation:** PKG, a major downstream effector of cGMP, can be regulated by phosphorylation or by binding of inhibitory proteins.
* **Desensitization of downstream targets:** Prolonged exposure to cGMP can lead to desensitization of downstream signaling pathways, reducing their responsiveness to subsequent cGMP stimuli.

4. **Feedback loops:** Negative feedback loops can dampen cGMP signaling. For example, the activation of PKG can lead to the phosphorylation and inhibition of GCs, thus reducing cGMP production.

5. **Competing signaling pathways:** Other second messenger systems, such as cAMP or calcium signaling, can antagonize or modulate cGMP-mediated signaling.

6. **Protein-protein interactions:** Specific protein-protein interactions can sequester or inhibit cGMP-binding proteins, disrupting cGMP signaling cascades.

By employing these diverse mechanisms, cells maintain tight control over cGMP signaling, ensuring appropriate responses to physiological stimuli and preventing aberrant signaling that could lead to cellular dysfunction or disease.'
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Proteins (4)

Compounds (80)