Gasotransmitter

Gasotransmitter are under standard conditions, gaseous substances that are synthesized in cells and play an important role in intercellular communication. Among them, nitric oxide ( NO), hydrogen sulfide (H2S ), carbon monoxide (CO ) and possibly nitrous oxide (laughing gas N2O).

General

Gasotransmitter belong to a family of endogenous molecules gas or gaseous signaling molecules, as NO, CO, H2S, and others. These gases have many features in common in their cellular production and function, also they are characterized in their biological functions in a unique way, which distinguish them from classical signaling molecules. Their distribution is ubiquitous from unicellular to multicellular organism, they are found in all domains. There are phylogenetically considered very old cellular communication principles.

For the first time exhibited in 1981 a clinical work back to the pharmacological effects of Gasotransmitter to corresponding receptors and as a neurotransmitter.

An in- vitro experiment confirmed these observations. A binding terminology and characterization for the criterion " Gasotransmitter " was introduced in 2002.

A gas can be categorized as Gasotransmitter when its molecules meet the following criteria:

• They are small.
• They are free of blockages, permeable to biological membranes. You have endocrine, paracrine and autocrine effects. In its endocrine mode of action of approximately Gasotransmitter can be released from tissues in the bloodstream and then spread unfold modulating functions on distant target cells.
• They are produced endogenously and enzymatically, and their production is regulated.
• They are chemically defined and have specific functions in physiologically relevant concentrations. Thus, they call in endogenous levels forth specific physiological changes.
• Their physiological and cellular functions can be mimicked by exogenously administered molecules.

Biological synthesis and action of nitric oxide (NO)

NO is produced enzymatically by the action of the various NO- synthases (NOS as NOS-I, NOS -II and the NOS -III) from the amino acid L-arginine.

The small molecule NO is highly reactive chemical and thus destabilizing for the biochemical structures of cells. This makes evolutionary terms a precise regulation of NO production sense. Two main principles of the NO mechanism of action are described:

• NO effect on metalloproteins, more particularly, to metal ions in the center of these proteins, for example enzymes and increase or decrease their activity,
• NO produces a protein nitrosylation, thereby the NO molecule is bound to an-SH or-S- CH 3 group at the sulfur atom. This triggers a conformational and which resulted in a change in function of the protein.

The released NO acts intracellularly via the activation of soluble guanylyl cyclases and, consequently, with an increase in intracellular production of the second messenger cyclic guanosine monophosphate ( cGMP).

Biological synthesis and effect of carbon monoxide ( CO)

In the organism, the CO molecule is formed to about 86 % by the oxidative degradation of the heme molecule with the simultaneous release of iron ( Fe2 and then ferritin) and biliverdin.

Heme b 3O2 NADPH 3 3 ½ ½ H → biliverdin 7e - Fe2 CO 3 ½ NADP 3H2O

Biliverdin

Only 14 % of endogenous CO derived from the photo-oxidation, lipid peroxidation and bacteria.

The heme - degrading enzyme heme oxygenase can be found in almost all animal tissues in vertebrates, mainly in the spleen. Based on the current state of research three isoforms are known.

• The inducible heme oxygenase-1 (also known as heat shock protein 32) can be up-regulated by various agents; this is approximately the heme molecule ( positive feedback), various heavy metals, growth factors, the NO molecule, various lipids under hypoxia.
• The constitutive HO-2 in various organs and tissues of these organs, such as the central nervous system, endothelial and the testes.

And the CO molecule may activate the soluble guanylate cyclase and an increase in the production of intracellular cGMP its intracellular effects auslösen.Das CO molecule influences the cGMP but to a lesser extent than would be the NO molecule, the activation is by CO only factor 4-5; in comparison, NO causes a 200 -fold activation.

Biological synthesis of hydrogen sulfide (H2S)

Hydrogen sulfide is synthesized in the cells from the amino acid L-cysteine ​​by the action of the enzymes cystathionine γ - lyase (CSE ) (EC 4.4.1.1 ) or cystathionine β - synthase (CBS).

Cysteine ​​ H2O → serine H2S

The gas, once released, rapidly reacts with thiol groups of the proteins present in the environment ( Cys - will - CySSH ), thereby changing their biological activity ( conformational change ). In particular, the cytochrome -c oxidase is thereby deactivated. The majority, however, is oxidized in the mitochondria via thiosulfate and sulfite to sulfate, or processed on Cysteinsulfinat to sulfite / sulfate or taurine. Enzymes which are found in various tissues or organs, such as in vascular system, liver, kidneys and brain are for H2S production in the area. In the latter organ also the highest H2S concentrations are found.