Secondary messengers are molecules that transduce a signal from a bound receptor to its site of action (e.g. the nucleus). There are essentially four mechanisms by which secondary messengers act but they cross talk and are rarely activated independently of each other. These mechanisms are cyclic AMP, IP3/DAG, Ca2+ ions and protein phosphorylation.

Cyclic AMP, IP3/DAG and Ca2+ ions

The generation of cAMP by G-protein-linked receptors results in an increase in cellular cAMP, which binds and activates specific cAMP-binding proteins. These dimerize and enter the cell nucleus to interact with set DNA sequences (the cAMP response elements). In addition, cofactors in the cAMP-binding proteins are co-activated and interact with the phosphorylation pathway.

Other G-protein complexes activate inner membrane-bound phospholipase complexes. These in turn cleave membrane phospholipid-polyphosphoinositide (PIP2) into two components. The first is the water-soluble molecule inositol trisphosphate, IP3. This floats off into the cytoplasm and interacts with gated ion channels in the endoplasmic reticulum (or sarcoplasmic reticulum in muscle cells), causing a rapid release of Ca2+. The lipid-soluble component diacylglycerol (DAG) remains at the membrane, but activates a serine/threonine kinase, protein kinase C (see phosphorylation section further).

Although the cellular calcium-binding proteins and ion pumps rapidly remove Ca2+ from the cytoplasm back into a storage compartment (such as the endoplasmic reticulum), free Ca2+ interacts with target proteins in the cytoplasm, inducing a phosphorylation/dephosphorylation cascade, resulting in activated DNA-binding proteins entering the nucleus.

Protein phosphorylation

Although phosphorylation of the cytoplasmic secondary messengers is often a consequence of secondary activation of cAMP, Ca2+ and DAG, the principal route for the protein phosphorylation cascades is from the dimerization of surface protein kinase receptors, which have bound their ligands. The tyrosine kinase receptors phosphorylate each other when ligand binding brings the intracellular receptor components into close proximity. The inner membrane and cytoplasmic targets of these activated receptor complexes are ras, protein kinase C and ultimately the MAP (mitogen activated protein) kinase, Janus-Stat pathways or phosphorylation of IκB causing it to release its DNA-binding protein, nuclear factor kappa B (NFκB). These intracellular signalling proteins usually contain conserved non-catalytic regions called SH2 and SH3 (serc homology regions 2 and 3). The SH2 region binds to phosphorylated tyrosine. The SH3 domain has been implicated in the recruitment of intermediates that activate ras proteins. Like G-proteins, ras (and its homologous family members rho and rac) switches between an inactive GDP-binding state and an active GTP-binding state. This starts a phosphorylation cascade of the MAP kinase, Janus-Stat protein pathways, which ultimately activate a DNA-binding protein (NFκB). NFκB undergoes a conformational change, enters the nucleus and initiates transcription of specific genes.

Lipid-soluble ligands (e.g. steroids) do not need secondary messengers; their cytoplasmic receptors, once activated, enter the nucleus as DNA-binding proteins and alter gene expression directly.

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1. [...] PER … Only the amino acids serine, threonine, and tyrosinase can be phosphorylated this way. …Health Nova: Your Ultimate Medical Portal SECONDARY MESSENGERSThe lipid-soluble component diacylglycerol (DAG) remains at the membrane, but activates a [...]

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