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Hydrophilic ligands like hormones and neurotransmitters cannot cross the cell membrane, so their messages must be relayed by second messengers inside the cell. Second messengers amplify and transmit signals from cell surface receptors to intracellular targets, enabling a cellular response. This system allows cells to respond to external signals without the ligand entering the cytoplasm.

When hormones or neurotransmitters bind to G-protein coupled receptors, they activate phospholipase C. This enzyme hydrolyzes phosphatidylinositol biphosphate (PIP2) in the plasma membrane, producing two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). This single enzymatic reaction generates both signaling molecules simultaneously.

DAG remains in the plasma membrane where it recruits and activates protein kinase C (PKC). IP3 diffuses through the cytoplasm and binds to IP3 receptors on the endoplasmic reticulum, triggering calcium ion release. These calcium ions then activate PKC, which phosphorylates other intracellular proteins to produce the cellular response.

G-protein coupled receptors activate phosphoinositol and cyclic AMP (cAMP) pathways. The phosphoinositol pathway produces DAG and IP3, while the cAMP pathway generates multiple cAMP copies from ATP molecules. Additionally, cyclic GMP (cGMP) is synthesized from GTP when guanylyl cyclase is activated, and PIP3 is generated when growth factors bind receptor tyrosine kinases.

When adenylate cyclase is activated by G-protein coupled receptors, it produces multiple copies of cAMP from ATP molecules. cAMP can stimulate protein kinase A (PKA), open calcium ion channels, and activate Exchange-protein activated by cAMP (Epac). This amplification allows a single receptor activation to generate numerous cAMP molecules, intensifying the signal.

cGMP is synthesized from guanosine triphosphate (GTP) when guanylyl cyclase is activated. 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 signaling to specific cell types.

PIP3 is generated when growth factors bind receptor tyrosine kinases, triggering phosphorylation of PIP2. PIP3 recruits Akt (protein kinase B) to the membrane, where it regulates critical cell survival pathways including proliferation, apoptosis, and migration. This positioning allows Akt to control whether cells survive, divide, or undergo programmed death.