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2. Definere begreberne signal transduktionsveje og "second messangers" og beskriv signal transduktionsveje via protein kinaser
http://ghr.nlm.nih.gov/ghr/glossary/signaltransduction
http://ghr.nlm.nih.gov/ghr/glossary/secondmessenger
Stryer, s.398

Signal transduction pathways - The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel.

Second messangers

- A diverse family of low molecular weight compounds such as cyclic AMP and calcium ions, which transmit the biological signals initiated by receptor-ligand binding at the cell surface to intracellular targets such as gene expression.

- Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system.

The highly specific binding of signal molecules, many of which hormones and growth factors, to receptor molecules initiates the signal-transduction cascade. Secondary messengers carry the signal inside the cell and often use protein phosphorylation as a signaling device.

Signaltransduktionsveje via protein kinazer
Devlin, s. 417
Devlin, s.925-6, fig.21.17
Devlin, s.943
 

Kinases - transferase enzymes. They catalyse the transfer of the chemically labile γ-phosphoryl group from ATP or other nucleoside triphosphate to alcohol or aminogroup acceptors.

Protein kinase - enzymes that are capable of transfering the γ-phosphoryl group from ATP to serin, threonin or thyrosin. The process is called phosphorylation.

Many amino acid-derived hormones bind to the cell membrane receptors and transmit their signal by:

• elevation of cAMP and transmission through the protein kinase A pathway (described below)

• triggering of the hydrolysis of phosphatidylinositol 4,5 - biphosphate and stimulation of the protein kinaze C pathway

• phosphorylation of tyrosine through the tyrosin kinase pathway (described below)

In other cases, the kinase is phosphorylated by the receptor itself (acting as a kinase), gets activated and is capable of phosphorylating other kinases and in that way forwarding the original signal. (tyrosin kinase pathway)

Protein Kinase A pathway
Devlin, s.927-8; fig. 21. 18
Stryer, s.403
 

Protein Kinase A pathway is activated by the generation of cAMP. The cAMP is released when a signal molecule binds to the membrane receptor causing several confirmational changes.

The receptor molecules on the cell membrane are usually built up of seven transmembrane proteins, which have an intra- and extracellular binding domain. The extracellular binding domain serves for binding signal molecules, while the intracellular domain has a site for binding G-proteins (GTP-binding proteins).

When the receptor is inactive, the G-protein consists of 3 units (α, β and γ) .

The α-subunit is the guanine nucleotide-binding unit. It has two binding domains that interact:

• indirectly with the receptor through the β and γ subunit

• directly to an enzyme which it activates

 When a signal molecules interacts with the receptor molecules the following happends:

step 1 - the hormone binds to a receptor in the membrane.

step 2 - this produces a confirmational change in the receptor and exposes the site for G-protein attachment (β and γ subunit)

step 3 - when the G-protein binds to the receptor, the α-subunit exchanges GDP for GTP

step 4 - disassociation of GTP causes separation of the α-subunit from the G-protein. The subunit migrates towards the enzyme and the enzyme-binding site appears.

step 5 - the binding of the α-subunit to the enzyme adenylate cyclase causes conversion of ATP into cAMP (cAMP is used in the protein kinaze A pathway)

step 6 - the α-subunit catalyses the conversion of GTP to GMP, which returns the α-subunit in its original state

The cAMP created from this transductional patway activates protein kinase A.

Four cAMP molecules are used in the reaction to activate protein kinase A. Under noramal circumstances, the enzyme consists of 2 regulatory and 2 catalytic subunits.
When the cAMP molecules bind to the enzyme, the 2 regulatory units bind together and the two catalytic units are released. The catalytic units are capable of phosphorylation of serine and threonine residues of proteins, that way having an effect on the target cell.

The increased concentration of cAMP can affect a wide range of cellular processes.
fx. it enhances the degradation of storage fuels, increases the secretion of acid by gastric mucosa, leads to despersion of melanin pigment granules, diminishes the agregation of blood platelets, and induces the opening of cloride channels.

Tyrosin Kinase Pathway
Devlin, s.943-5; fig.21.36
Stryer, s.414

The tyrosin specific kinazes are transmembrane receptor proteins, that, when activated by the binding of specific extracellular ligands (usually growth factors), phosphorylate proteins (including themselves) on tyrosin residues inside the cell.

The typical example of the tyrosin kinase pathway is the effect of insulin on the cell.

• The insulin receptor on the plasma membrane is made up of two α and two β subunits. The α subunits are located on the outside of the cell, while the β-subunits are transmembrane segments.
   

• When insulin binds on the α-subunits, the conformational change of the receptor induces phosphorylation of the tyrosin residues of the β-subunt (autophosphorylation).
   

• The β-subunit is now able to phosphorylate other cytosolic proteins. The subsequent phosphorylations occur predominantly on serine and threonine residues. The final result is increased growth.
   

• However, insulin can also have a dephosphorylating effect, by inducing a second-messanger effect, that activated a phosphatease, that dephosphorylates proteins. The final result is increased metabolism

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