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Second messengers are low molecular weight non-protein molecules that relay signals from cell surface receptors to targets within the cell. They are necessary because many ligands are hydrophilic and cannot cross the cell membrane, so their message must be relayed by second messengers present in the cytoplasm. Examples include calcium ions, cyclic AMP, and inositol trisphosphate.

In the phosphoinositol pathway, G protein-coupled receptors activate phospholipase C, which hydrolyzes phosphatidylinositol biphosphate (PIP2) into two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). DAG remains near the cell membrane and activates protein kinase C, while IP3 translocates to the endoplasmic reticulum to release calcium ions.

Cyclic AMP (cAMP) is produced by adenylyl cyclase when activated by G protein-coupled receptors. Multiple copies of cAMP are generated from ATP molecules, allowing signal amplification. cAMP can stimulate protein kinase A, open calcium ion channels, and activate the enzyme Exchange-protein activated by cAMP (Epac).

Second messengers amplify signals by activating multiple downstream kinases and enzymes. For example, a single activated receptor can trigger adenylyl cyclase to produce many cAMP molecules, and each cAMP molecule can activate protein kinase A, creating an amplifying signals via enzymatic cascade effect that magnifies the original signal.

Calcium ions are widely occurring second messengers that trigger diverse physiological functions when intracellular concentration increases in response to specific signals. In muscle cells, increased cytosolic calcium results in muscle contraction. Calcium can be released from the endoplasmic reticulum through IP3-activated channels or through other calcium ion channels.

Phosphatidylinositol triphosphate (PIP3) is a second messenger derived from phosphorylation of PIP2 when growth factors bind receptor tyrosine kinases. Unlike other second messengers, PIP3 recruits Akt (protein kinase B) to the membrane, where it regulates cell survival pathways including proliferation, apoptosis, and migration.

Cyclic GMP (cGMP) is synthesized from GTP when guanylyl cyclase is activated, similar to how cAMP is produced. As a second messenger, cGMP induces protein kinase G (PKG), which has overlapping functions with protein kinase A. However, PKG expression is restricted to vascular tissues, lungs, and the brain, limiting cGMP's physiological scope.