Signaling using NO, medical relevance

Nitric oxide (NO) is a highly reactive signaling molecule with a very short half-life (a few seconds). It plays important roles in many physiological processes.

Production of NO

NO is produced in various tissues by enzymes called nitric oxide synthases (NOS). These are complex proteins requiring multiple cofactors and prosthetic groups:

• FMN
• FAD
• Non-heme iron
• Tetrahydrobiopterin
• Heme

NOS enzymes catalyze the synthesis of NO from arginine, in the presence of NADPH + H⁺ and oxygen (O₂).

There are several isoforms of NOS:

• Neuronal and endothelial NOS - calcium-dependent.
• Inducible NOS - calcium-independent, expressed in immune system cells and endothelial cells during inflammation.

Mechanism of action

cGMP Pathway

cGMP-mediated pathway

Inside cells, NO activates guanylate cyclase, which increases the production of cyclic GMP (cGMP), which then activates protein kinase G (PKG), leading to physiological effects such as:

• Relaxation of vascular smooth muscle
• Vasodilation and increased blood flow

This mechanism is similar to the action of atrial natriuretic peptide (ANP), which also increases cGMP, but by directly stimulating guanylate cyclase through the ANP receptor.

Protein nitrosylation

Due to its high reactivity, NO can modify proteins by interacting with amino acids, forming nitrosylated derivatives.

This nitrosylation acts as a regulatory mechanism, much like phosphorylation, influencing protein function.

• For example nitrosylation of caspases inhibits apoptosis in various cell types.

Cytotoxic effects in the immune system

In macrophages, NO serves as a cytotoxic agent against pathogens. The production and release of NO contribute to the defense mechanisms of the immune response.

Medical Significance

Angina pectoris

• Nitroglycerin (glycerol trinitrate), used to treat angina pectoris, releases NO into the bloodstream. This causes vasodilation, reduces cardiac workload, and improves myocardial oxygen supply.

Erection

• During sexual arousal, local NO release increases cGMP levels in the penile tissue, leading to smooth muscle relaxation and increased blood flow, enabling erection. After stimulation, cGMP is rapidly degraded by cGMP-specific phosphodiesterase (PDE5).

Viagra and related drugs

• These medications inhibit PDE5, preventing cGMP breakdown and thus prolonging the erection

Sources

MATOUŠ, Bohuslav, et al. Základy lékařské chemie a biochemie. 1. vydání. Praha : Galén, 2010. 540 s.