nitric oxide-cGMP-mediated signaling

Definition

Target type: biologicalprocess

An intracellular signaling cassette in which the signal is passed on within the cell by nitric oxide (NO) activating soluble guanylyl cyclase (sGC). Includes synthesis of nitric oxide, guanylyl cyclase activity, and downstream effectors that further transmit the signal within the cell following activation by cGMP. [GOC:signaling, PMID:21549190, PMID:22019632]

Nitric oxide (NO) signaling is a crucial cellular communication pathway involved in a wide range of physiological processes, including vasodilation, neurotransmission, inflammation, and immune responses. The process is initiated by the production of NO, a highly reactive gas molecule synthesized from L-arginine by nitric oxide synthase (NOS) enzymes. There are three main isoforms of NOS: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). Each isoform is localized to specific cell types and is regulated by distinct signaling pathways.

Once produced, NO diffuses rapidly across cell membranes and binds to its primary target, soluble guanylate cyclase (sGC), an enzyme that converts GTP to cyclic GMP (cGMP). The binding of NO to sGC activates the enzyme, leading to a rapid increase in intracellular cGMP levels. cGMP, a second messenger molecule, then triggers downstream signaling cascades that mediate the diverse effects of NO.

cGMP signaling is primarily mediated through the activation of cGMP-dependent protein kinases (PKG), which phosphorylate specific target proteins, altering their activity. PKG activation leads to a variety of downstream effects, including:

1. **Vasodilation:** NO-induced cGMP production relaxes vascular smooth muscle cells, resulting in vasodilation and improved blood flow. This effect is crucial for maintaining blood pressure and regulating blood flow to various organs.

2. **Neurotransmission:** NO plays a key role in neurotransmission by modulating synaptic plasticity, neuronal survival, and neuroprotection. It acts as a retrograde messenger, traveling from the postsynaptic neuron back to the presynaptic neuron, where it regulates neurotransmitter release and synaptic strength.

3. **Inflammation and Immune Response:** NO is involved in both pro-inflammatory and anti-inflammatory responses. It can activate immune cells, such as macrophages and neutrophils, but also regulate the inflammatory cascade by inhibiting the production of pro-inflammatory cytokines.

4. **Cell Growth and Proliferation:** NO can promote cell growth and proliferation in certain tissues, while inhibiting it in others. It plays a complex role in regulating cell cycle progression and apoptosis.

In addition to PKG, cGMP can also interact with other signaling pathways, including cyclic nucleotide-gated ion channels and phosphodiesterases. These interactions contribute to the diverse effects of NO signaling in various cell types.

NO signaling is highly regulated and tightly controlled to prevent excessive or uncontrolled activation. The production of NO is tightly regulated by the activity of NOS enzymes, and cGMP levels are controlled by the activity of phosphodiesterases, which break down cGMP.

Dysregulation of NO signaling has been implicated in various pathological conditions, including hypertension, cardiovascular disease, stroke, neurodegenerative disorders, and inflammatory diseases. Therefore, understanding the complex mechanisms of NO-cGMP signaling is crucial for developing targeted therapies for these conditions.'
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Proteins (4)

Compounds (35)