Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces phospholipase C to hydrolyze the phospholipid, phosphatidylinositol biphosphate (PIP₂), into two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP₃). DAG remains near the cell membrane and activates protein kinase C (PKC). IP₃ translocates to the endoplasmic reticulum (ER) and becomes the opening ligand for calcium ion channels on the ER membrane, releasing calcium into the cytoplasm.

In the cAMP pathway, the activated receptor induces adenylate cyclase to produce multiple copies of cAMP from nearby adenosine triphosphate (ATP) molecules. cAMP can stimulate protein kinase A (PKA), open calcium ion channels, and activate the enzyme– Exchange-protein activated by cAMP (Epac).

Cyclic guanosine monophosphate (cGMP) is similar to cAMP. cGMP is synthesized from guanosine triphosphate (GTP) molecules when guanylyl cyclase is activated. As a second messenger, cGMP induces protein kinase G (PKG), which has many overlapping functions with PKA. However, PKG expression is restricted to vascular tissues, lungs, and the brain.

Phosphatidylinositol triphosphate (PIP₃) is a second messenger derived from the phosphorylation of PIP₂. This event is triggered when growth factors bind the receptor tyrosine kinase. PIP₃ recruits Akt (aka. protein kinase B) to the membrane. This kinase is intimately involved in regulating cell survival pathways– including proliferation, apoptosis, and migration.