4.2 Introduction to Signal Transduction

• Reception: a signal molecule, called a ligand, binds to a receptor protein on or in the target cell.
• Transduction: the receptor changes shape, which sets off a chain of changes inside the cell. Relay molecules pass the signal along, often amplifying it.
• Response: the signal produces a change in the cell, such as turning on genes, releasing (secreting) a molecule, or growing and dividing.

A ligand is any molecule that binds specifically to another molecule; here, it's the signal. The part of the receptor that binds it is the ligand-binding domain. The fit is very specific, a lot like an enzyme and its substrate (3.1). Ligands can be peptides (small proteins), like insulin, or small molecules, like epinephrine or steroid hormones.

Where the receptor sits depends on the ligand. Large or polar ligands can't cross the plasma membrane (2.4), so their receptors sit on the cell surface. Small nonpolar ligands, such as steroid hormones like testosterone and estrogen, pass through the membrane and bind receptors in the cytoplasm or nucleus. Many of these hormone-receptor complexes then act directly on DNA to turn genes on or off.

• G protein-coupled receptors (GPCRs): a large family of cell-surface receptors in eukaryotes. When a ligand binds, the receptor changes shape and activates a G protein on the inside of the membrane. The activated G protein then switches on an enzyme, which starts the relay. GPCRs are an example of a receptor you should know by name.
• Ligand-gated ion channels: receptors that are also channels (2.6). When the ligand binds, the channel opens or closes, letting specific ions in or out. Many neurotransmitter receptors work this way.
• Intracellular receptors: receptors in the cytoplasm or nucleus for ligands that can cross the membrane, as described above.

After the ligand binds, the part of the receptor inside the cell changes shape. That starts the relay.

Protein kinases are enzymes that add phosphate groups (from ATP) to other proteins, which is called phosphorylation. Phosphorylation changes a protein's shape and usually switches it on. In a phosphorylation cascade, one kinase activates the next, which activates the next, like a line of falling dominoes. Enzymes called phosphatases remove the phosphates, which switches the proteins back off so the signal doesn't last forever.

Second messengers are small, non-protein molecules that spread quickly through the cell to carry the signal. Cyclic AMP (cAMP) is a key one. In many GPCR pathways, the activated G protein switches on an enzyme that converts ATP into cAMP, and cAMP then activates a protein kinase.

Signals are usually amplified. One activated receptor can activate many G proteins, each enzyme they switch on can make many cAMP molecules, and each kinase can phosphorylate many proteins. So a few ligand molecules outside can change millions of molecules inside.

When you're frightened, epinephrine (adrenaline) is released into your blood. In a liver cell, it binds a GPCR. The G protein activates an enzyme that makes cAMP, cAMP activates a protein kinase, and a phosphorylation cascade activates the enzyme that breaks glycogen into glucose. The liver releases the glucose into the blood, fueling your muscles for 'fight or flight.' Epinephrine never enters the cell; the message is carried entirely by the relay inside.