7.1 Receptors, Transduction and Feedback

Large, polar or charged ligands cannot cross the hydrophobic core of a phospholipid bilayer readily, so peptide hormones and most neurotransmitters bind transmembrane receptors. A surface receptor exposes an extracellular binding region, crosses the membrane and communicates with proteins on the cytoplasmic side. Small non-polar ligands such as steroid hormones diffuse through the bilayer and bind intracellular receptors in the cytosol or nucleus.

This distinction predicts response style but not every detail. Surface receptors often change existing proteins rapidly through channels or phosphorylation. Intracellular receptor complexes commonly regulate transcription, so their effects require RNA and protein synthesis and tend to develop more slowly. Yet both routes are selective, both can be amplified, and both ultimately alter molecular activity in a target cell.

At many cholinergic synapses, acetylcholine binds a ligand-gated receptor whose conformational change opens an ion channel. Cations then move down electrochemical gradients, changing membrane potential. The receptor does not pump the ions and acetylcholine does not carry electrical charge along the axon. Chemical binding changes permeability; existing gradients supply the directional driving force.

A G-protein-coupled receptor changes shape after ligand binding and activates a membrane-associated G protein by promoting GDP–GTP exchange. The active G protein can stimulate adenylyl cyclase, which converts ATP to cyclic AMP. cAMP is a second messenger because it carries information within the cell. It activates protein kinase A, and the kinase phosphorylates target proteins.

Epinephrine uses this route in liver cells to promote glycogen breakdown and inhibit glycogen synthesis, making glucose available during a fight-or-flight response. The same second messenger need not produce the same outcome elsewhere: a cell's response depends on which protein kinase targets and metabolic enzymes it expresses. Signal identity, receptor subtype and internal molecular context jointly determine the outcome.

The insulin receptor has tyrosine kinase activity. Insulin binding changes the receptor and causes phosphorylation on cytoplasmic tyrosine residues. Intracellular proteins bind to the phosphorylated receptor and start a cascade that includes movement of vesicles bearing glucose transporters to the plasma membrane in responsive tissues. More transporters increase the membrane's capacity for facilitated glucose uptake; phosphorylation supplies regulation, not glucose energy.

A steroid crosses the membrane, binds a receptor and changes the receptor's conformation. The ligand–receptor complex can enter the nucleus or act there directly, bind specific DNA regulatory sequences and recruit proteins that raise or lower transcription of target genes. Intracellular receptors therefore include ligand-binding, DNA-binding and transcription-regulating regions. They do not switch on every gene: DNA sequence, chromatin accessibility and co-regulators constrain the response.

Negative feedback reduces the deviation that triggered a response. Rising blood glucose stimulates insulin release; insulin-dependent uptake and storage lower glucose, so the stimulus to β cells declines. Positive feedback reinforces a change. Oxytocin-driven uterine contractions increase cervical stretch, promoting further oxytocin release until birth ends the loop. The sign of feedback is defined by its effect on the initial change, not by whether the outcome is beneficial.