Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. Continuation of a signal in this manner is called signal transduction.

When a ligand binds to its receptor, conformational changes occur that affect the receptor’s intracellular domain. Conformational changes of the extracellular domain upon ligand binding can propagate through the membrane region of the receptor and lead to activation of the intracellular domain or its associated proteins.

Binding Initiates a Signaling Pathway

After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a signaling pathway, sometimes called a signaling cascade. In a signaling pathway, second messengers–enzymes–and activated proteins interact with specific proteins, which are in turn activated in a chain reaction that eventually leads to a change in the cell, such as an increase in metabolism or specific gene expression. The events in the cascade occur in a series of steps. Interactions that occur before a certain point are defined as upstream events, and events after that point are called downstream events.

Methods of Intracellular Signaling

The induction of a signaling pathway often depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur, and they are recognized in turn by the next component downstream. The following are some of the more common events in intracellular signaling.

Phosphorylation

One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO₄^–3) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins, where they replace the hydroxyl group of the amino acid. The transfer of the phosphate is catalyzed by an enzyme called a kinase. Various kinases are named for the substrate they phosphorylate. Phosphorylation of serine and threonine residues often activates enzymes. Phosphorylation of tyrosine residues can either affect the activity of an enzyme or create a binding site that interacts with downstream components in the signaling cascade. Phosphorylation may activate or inactivate enzymes, and the reversal of phosphorylation, dephosphorylation by a phosphatase, will reverse the effect.

Second Messengers

Second messengers are small molecules that propagate a signal after it has been initiated by the binding of a signaling molecule to its receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely used second messenger. The free concentration of calcium ions (Ca²⁺) within a cell is very low because ion pumps in the plasma membrane continuously remove it. For signaling purposes, Ca²⁺ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca²⁺ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca²⁺. The response to the increase in Ca²⁺ varies and depends on the cell type involved. For example, in the β-cells of the pancreas, Ca²⁺ signaling leads to the release of insulin, and in muscle cells, an increase in Ca²⁺ leads to muscle contractions. In other cells, it leads to transcription.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP). Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP. The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase). A-kinase regulates many vital metabolic pathways: It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells, and the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.