Second messenger system

Second messenger is an English technical term in biology and medicine, which may be translated into German with second messenger. Also second messenger or secondary signal are in the literature encountered, synonymous terms. A second messenger is an intracellular chemical substance whose concentration in response to a primary signal (" first messenger " = ligand) is changed.

The second messenger is the intracellular routing of a coming from the outside ( extracellular) primary signal can not pass through the cell membrane. Serves the primary signal of the signal transmission between cells, so is the second messenger signal transduction within the cell, ie, intracellularly. Here, the second messenger is often only the beginning of one or more extended, intracellular signaling pathways, which are also used for signal amplification and eventually lead to a cellular response to the primary signal. Second Messenger were first described for the transduction of signals hydrophilic hormones such as insulin, glucagon, and epinephrine, or neurotransmitters such as glutamate.

Figure 1 exemplarily treated the two most common and oldest known second messenger systems (cAMP and IP3). Other members of the class are cyclic GMP ( cGMP, a cAMP analog nucleotide ), but also gases such as nitric oxide and (possibly) carbon monoxide.

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ATP is the precursor of the longest known secondary messenger molecule cyclic AMP (cAMP ). NO is produced by adenylyl cyclase ( adenylate cyclase, AC), which is activated in turn, often by the α - subunit of a G protein (Gs ).

Effect

The effect of cAMP is mainly due to the activation of cAMP-dependent protein kinase A (PKA), which transfers phosphate groups to proteins. These phosphorylated proteins may exert different functions.

Reduction

The life of cAMP is limited by the large family of phosphodiesterases (PDE ). The known effects of caffeine go - at least partially - on back that this methylated xanthine is an inhibitor of PDE. cAMP is therefore not degraded so quickly. On the other hand there is an effect of insulin in the activation of PDE in the liver. This reduces the cAMP concentration and at the same time providing glucose.

Cyclic guanosine monophosphate ( cGMP) as a second messenger

Cyclic guanosine monophosphate ( cGMP), is chemically very similar to the cAMP and cAMP analog is produced by a guanylyl cyclase from GTP. The guanylyl cyclase can be either membrane bound or soluble present. cGMP exerts two functions. It can activate cGMP -dependent protein kinases or affect the opening state of cation channels. The latter plays, for example, in the visual signal transduction, ie in vision in the light-sensitive cells, an important role. The cellular response to exposure is here but not the up- but the degradation of cGMP! A single absorbed photon can cause a G protein- coupled process for the hydrolysis of about a hundred thousand cGMP molecules.

Inositol -1 ,4,5 -triphosphate ( IP3) as a second messenger

Another important and this widespread signaling system is derived from the phospholipids of the cell membrane, especially of Phosphatidylinositolbisphosphat ( PIP2 ). In this signal transmission not adenylate cyclase, but the membrane-bound enzyme phospholipase C ( PLC) is activated by the G protein. This cleaves PIP2 into inositol triphosphate (IP3 ) and diacylglycerol (DAG ). The first effect on the activation of IP3 receptors, the release of calcium ions from intracellular calcium stores ( for example, ER ), the latter, together with calcium, an activator of the Ca2 -dependent protein kinase C ( PKC). As the protein kinase A proteins are phosphorylated by protein kinase C now. The effects are similarly diverse. This mechanism is, inter alia, in the contraction of skeletal muscle in response to the neurotransmitter acetylcholine into play. An alternative processing PIP2 - related phospholipids lies in the elimination of arachidonic acid ( ARA) by phospholipase A2 ( PLA2). Arachidonic acid (C20: 4) on the one hand stimulates secretory and on the other hand the source of prostaglandins, a particular class of tissue hormones.

Calcium ions as second messengers

Calcium ions ( Ca2 ) are key signaling molecules within the cell, even though they do not usually stand at the beginning of an intracellular signaling cascade. Hormones or by electrical stimulation, an increase of the calcium concentration of the cell can occur. The free calcium ion concentration is extremely low in a non-excited cell in comparison with the external medium. The opening of specific ion channels, the concentration can be increased by several orders of magnitude.

Calcium ions have a variety of different effects, and have many important processes, such as the contraction of muscles during cell division, secretion, gene expression or in response to the intermediary metabolism. In plants, inter alia, in the induction of specific growth processes, it plays an important role.

Calcium ions can act in two different ways as a signaling molecule. Either include target molecules such as protein kinase C, phospholipase A2 or villin a specific binding site for calcium ions. The activity of these molecules is directly influenced by the calcium ions. One in all eukaryotes occurring and widespread target protein is calmodulin, which can bind four calcium ions. This may in the calcium -bound state in turn attach to other proteins and activate those. Here calcium is indirect.

Nitric oxide (NO ) as a second messenger

The gaseous nitrogen monoxide (NO ) may also act as second messengers. Originally, the importance of NO was discovered as a chemical messenger associated with the contraction and relaxation of blood vessels. It is now known that almost every cell can be regulated in mammals by NO and that it serves as a universal signal for the intra-and intercellular communication.

NO is formed enzymatically from the amino acid L- arginine, which catalyzes a nitric oxide ( NO synthase, NOS). This results in citrulline which can be regenerated in the urea cycle back to arginine. The NO synthases are active as dimers and can be present as inactive monomers. There are three different NO synthases, which respond differently sensitive to calcium ions. A shape NOS II, but in this case not regulated by calcium ions, but by the transcription of its mRNA. NO synthase requires various cofactors such as FAD, heme and / or oxygen.

NO is a small, water-soluble molecule that can pass through biomembranes freely. Since it is present as radical, it has water in only a short lifetime of about 4 seconds. It reacts with oxygen, Fe (II) hemes and SH groups, which results in the formation of S- nitrosyl (RS -NO) by itself. Bound enzyme is NO stable much longer than free in solution.

By an extra - or intracellular signals, the formation of NO is stimulated. It can serve within the same cell as a messenger or a trigger signal from a neighboring cell. Therefore, it has both autocrine or paracrine the property of a hormone, as well as an intracellular messenger.

Physiologically NO exerts from a regulatory and toxic function. The latter in particular in the nervous system plays a role. Maybe for a stroke, an increased amount of NO is formed, which leads to the death of nerve cells.

The regulatory role of nitric oxide is varied, as it can react with many effector proteins. Thus, NO can activate, for example, an NO - sensitive guanylyl cyclase, so that the amount of cGMP increases. This has many consequences ( see above). Another effector molecule is hemoglobin which can be nitrolysiert to a reactive cysteine ​​, Cys 93, and the iron atom by NO. Through these processes, the erythrocytes can store nitrogen monoxide and transported through the blood vessels. In dependence on the oxygen content NO dissociated again and is able to react with glutathione, or other cysteines. This NO finally enters the endothelium of small blood vessels where it causes a dilation of blood vessels.