Second Messenger

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

The second messenger is used for the intracellular transmission of a primary signal coming from outside (extracellular) that cannot pass through the cell membrane. The primary signal carries signals between cells; the second messenger is used for signal transmission within the cell, so it is intracellular. The second messenger is often only at the beginning of one or more longer, intracellular signal chains that also serve to amplify the signal and ultimately lead to a cell response to the primary signal. Second messengers were initially used to transmit signals to hydrophilic hormones , such as B. insulin , glucagon and adrenaline , or neurotransmitters such as. B. Glutamate described.

Fig. 1: Second messenger systems: Second messenger (compounds framed in green), their formation from ATP or phosphatidylinositol bisphosphate (both shown in simplified form) and some target enzymes. Ca ⁺⁺ is also often classified as a second messenger, but is one level lower in the hierarchy (ie it is only released through the IP ₃ effect) - ARA = arachidonic acid ; DAG = 1,2-diacylglycerols

Figure 1 exemplifies the two most common and longest known second messenger systems (cAMP and IP ₃ ). Further representatives of the class are cyclic GMP (cGMP, a cAMP-analogous nucleotide ), but also gases such as nitrogen monoxide and (possibly) carbon monoxide .

Cyclic adenosine monophosphate (cAMP) as a second messenger

Fig. 2: Activation of gene transcription by cAMP as a second messenger.

education

ATP is the precursor of the longest known secondary messenger molecule, cyclic AMP (cAMP). This is formed by adenylyl cyclase (adenylate cyclase, AC), which in turn is often activated by the α-subunit of a G protein (G _s ).

effect

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

The phosphorylated proteins act as activated enzymes. An example of this is the cellular response of muscle cells to adrenaline . Glucose is released from glycogen within seconds .
The phosphorylated proteins serve as activated transcription factors or gene regulator proteins. A typical signal chain looks like this: hormone or neurotransmitter → receptor → G protein → adenylate cyclase → cyclic AMP (cAMP) → gene regulator protein → gene transcription → gene product (s) (see Figure 2). It can take minutes to hours from the primary signal to the cell response.

Dismantling

The lifespan of cAMP is limited by the large family of phosphodiesterases (PDE). The known effects of caffeine are - at least in part - due to the fact that this methylated xanthine is an inhibitor of PDE. So cAMP is not degraded as quickly. On the other hand, one effect of insulin is to activate the PDE in the liver . This reduces the cAMP concentration and at the same time the supply of glucose .

Cyclic guanosine monophosphate (cGMP) as a second messenger

Cyclic guanosine monophosphate (cGMP) is chemically very similar to cAMP and, analogous to cAMP, is produced by a guanylyl cyclase from GTP . The guanylyl cyclase can either be membrane-bound or soluble. cGMP has two functions. It can activate cGMP-dependent protein kinases or influence the state of the opening of cation channels. The latter plays z. B. in the visual signal transduction , so in the visual process in the light sense cells, an important role. The cell response to exposure is not the build-up, but the breakdown of cGMP! A single absorbed photon can lead to the hydrolysis of approximately one hundred thousand cGMP molecules via a G-protein-coupled process.

Inositol 1,4,5-trisphosphate (IP ₃ ) as second messenger

Another important and widely branched signal system is derived from the phospholipids of the cell membrane, here in particular from phosphatidylinositol bisphosphate (PIP ₂ ). During this signal transmission, it is not the adenylate cyclase but the membrane-bound enzyme phospholipase C (PLC) that is activated via the G protein . This splits PIP ₂ into inositol trisphosphate (IP ₃ ) and diacylglycerol (DAG). The former causes the release of calcium ions from intracellular calcium stores (e.g. from the ER ) via the activation of IP ₃ receptors ; the latter, together with calcium, is an activator of Ca ²⁺ -dependent protein kinase C (PKC). As with protein kinase A, protein kinase C now phosphorylates proteins. The effects are similarly diverse. An alternative processing of PIP ₂ -related phospholipids consists in splitting off arachidonic acid (ARA) by phospholipase A ₂ (PLA ₂ ). Arachidonic acid (C20: 4) stimulates secretion processes on the one hand and is the source of prostaglandins , a special class of tissue hormones , on the other .

Calcium ions as a second messenger

Calcium ions ( Ca ²⁺ ) are central signal ions within the cell, even if they are usually not at the beginning of an intracellular signal chain. Hormones or electrical stimulation can increase the calcium concentration in the cell. The free calcium ion concentration in a non-excited cell is extremely low compared to the external medium. By opening specific ion channels, the concentration can be increased by several powers of ten.

Calcium ions have a multitude of different effects and act on many important processes, for example during the contraction of muscles, during cell division, secretion, gene expression or when reacting with the intermediate metabolism. In plants, it plays an important role, among other things, in triggering certain growth processes.

Calcium ions can act as signaling molecules in two different ways. Target molecules such as protein kinase C , villin or phospholipase A2 either have a specific binding site for calcium ions. The activity of these molecules is directly influenced by the calcium ions. A common target protein found in all eukaryotes is calmodulin , which can bind four calcium ions. In the calcium-bound state, this can in turn dock onto other proteins and activate them. Calcium acts indirectly here.

Nitric oxide (NO) as a second messenger

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

NO is enzymatically formed from the amino acid L - arginine , which catalyzes a nitrogen monoxide synthase (NO synthase, NOS). This creates citrulline , which can be regenerated back to arginine in the urea cycle . The NO synthases are active as dimers and can exist as inactive monomers. There are three different NO synthases that have different sensitivities to calcium ions. One form, NOS II, is not regulated by calcium ions, but by the transcription of its mRNA. The NO synthase requires various cofactors, such as FAD , heme and / or oxygen.

NO is a small, water-soluble molecule that can freely pass through biomembranes. Since it is present as a radical , it only has a short lifespan of approx. 4 seconds in water. It reacts with oxygen, Fe (II) in heme and SH groups, which leads to the formation of S-nitrosyl groups (RS-NO). When bound to enzymes, NO is stable much longer than when it is free in solution.

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

Physiologically, NO has both a regulatory and a toxic function. The latter plays a role in the nervous system in particular. It is possible that an increased amount of NO is formed during a stroke , which leads to the death of nerve cells.

The regulatory function of nitric oxide is diverse, as it can react with many effector proteins. For example, NO can activate a NO-sensitive guanylyl cyclase, so that the amount of cGMP increases. This has various consequences (see above). Another effector molecule is hemoglobin , which can be nitrolysed by NO on a reactive cysteine group, Cys 93, and on the iron atom. These processes enable erythrocytes to store nitric oxide and transport it through the blood vessels. Depending on the oxygen content, NO dissociates again and can react with glutathione or other cysteines. As a result, NO finally reaches the endothelium of small blood vessels and causes these blood vessels to widen. The formed cGMP activates the protein kinase G, which then phosphorylates the Mysoin light chain kinase . The phosphorylated MLCK can no longer activate the myosin light chain in the smooth muscles, which is why contraction is not possible. The smooth muscles relax and thus vasodilation.

literature

Gerhard Krauss: Biochemistry of Signal Transduction and Regulation . Wiley-VCH Verlag GmbH & Co. KGaA; 4th expanded and improved edition 2008; ISBN 978-3-527-31397-6 , pp. 327ff.
Bruce Alberts, Dennis Bray, Karen Hopkin, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, Lutz Nover (ed.) And Pascal von Koskull-Döring (ed.): Textbook of Molecular Cell Biology . Wiley-VCH; 3rd completely revised edition 2005; ISBN 978-3-527-31160-6
Rolf Knippers: Molecular Genetics . Thieme, Stuttgart; 9., compl. revised Edition 2006; ISBN 978-3-13-477009-4

Web links

Signal transmission between cells (Mario Hupfeld)