A receptor is a protein — usually embedded in a cell membrane or located inside a cell — that detects a specific chemical signal and initiates a cellular response. Receptors are the molecular targets through which neurotransmitters, hormones, and most drugs produce their effects. They are the locks to which signaling molecules are the keys.
How receptors work
A receptor has a binding site — a region whose three-dimensional shape is complementary to the shape of its specific signaling molecule (called its ligand). When the ligand binds, the receptor changes shape (a conformational change), which triggers a cascade of events inside the cell. This might mean opening an ion channel, activating an enzyme, or initiating a gene expression program.
The specificity of the binding site is what makes receptor-mediated signaling precise. The mu-opioid receptor responds to endorphins (and to morphine, which mimics their shape) but not to serotonin. The serotonin 5-HT1A receptor responds to serotonin but not to dopamine. This specificity is also why drugs have “off-target” effects: at higher concentrations, a drug may begin binding to receptors it does not normally interact with at lower concentrations, producing side effects.
Major receptor families
Ligand-gated ion channels — receptors that are also ion channels. When the ligand binds, the channel opens, allowing ions (sodium, potassium, calcium, chloride) to flow across the membrane. These produce fast responses (milliseconds). Examples: GABA-A receptors (chloride channels; inhibitory; enhanced by benzodiazepines), NMDA receptors (calcium channels; excitatory; involved in central sensitization).
G-protein-coupled receptors (GPCRs) — the largest family of receptors and the most common drug targets. When the ligand binds, the receptor activates an intracellular G-protein, which triggers a signaling cascade. These produce slower responses (seconds to minutes) but can amplify the signal enormously. Examples: mu-opioid receptors, adrenergic receptors, dopamine receptors, most serotonin receptors.
Receptor tyrosine kinases — receptors that, when activated, add phosphate groups to intracellular proteins, initiating cascades that affect cell growth, differentiation, and survival. These are the targets of many cancer drugs. Responses are slow (hours to days).
Nuclear receptors — located inside the cell; bind ligands that can cross the cell membrane (steroid hormones, thyroid hormone, vitamin D). When activated, they directly regulate gene expression. Responses are the slowest (hours to days) but can produce lasting changes in cell behavior.
Receptors and sensory systems
The term “receptor” is used in two related but distinct ways in medicine:
- Molecular receptors — the proteins described above; the targets of neurotransmitters and drugs
- Sensory receptors — specialized nerve endings or cells that detect physical stimuli (touch, pressure, temperature, stretch, chemicals) and convert them into electrical signals
Sensory receptors include:
- Mechanoreceptors — detect pressure, vibration, stretch (Merkel cells in skin, muscle spindles in muscles, Golgi tendon organs in tendons)
- Thermoreceptors — detect temperature changes
- Nociceptors — detect potentially damaging stimuli (nociception)
- Chemoreceptors — detect chemical changes (oxygen/CO2 levels in blood, pH)
The connection between the two uses: sensory receptors contain molecular receptors. A nociceptor’s sensitivity to heat is mediated by a specific molecular receptor (TRPV1) that opens an ion channel in response to high temperature. Capsaicin (the compound that makes chili peppers hot) activates the same TRPV1 receptor, which is why hot peppers produce a sensation of burning — the molecular receptor cannot distinguish between actual heat and capsaicin.
Receptors as the basis of drug action
Nearly all of pharmacodynamics is receptor physiology applied to clinical practice. Agonists activate receptors. Antagonists block them. Partial agonists partially activate them. The therapeutic index reflects the difference between the dose that activates the desired receptor and the dose that begins activating unintended receptors. Drug interactions often involve two drugs competing for the same receptor or affecting the same receptor system through different mechanisms.