A peptide hormone circulating in the blood does nothing until it finds its receptor. For most peptide hormones and neuropeptides, that receptor is a G protein-coupled receptor (GPCR), a member of the largest family of cell-surface receptors in the human body.
The GPCR family
Humans have roughly 800 GPCR genes. They detect light, odours, tastes, hormones and neurotransmitters. They're also among the most important drug targets: roughly a third of approved medicines act on a GPCR. Robert Lefkowitz and Brian Kobilka shared the 2012 Nobel Prize in Chemistry for revealing how these receptors work.
Structure: seven passes through the membrane
Every GPCR crosses the cell membrane seven times as α-helices. The outside part binds the signal, and the inside part couples to signalling proteins. Peptide-binding GPCRs fall into two main groups:
- Class A (rhodopsin-like): peptides bind in a pocket formed by the helices. Examples include receptors for oxytocin, vasopressin, angiotensin and the opioid peptides.
- Class B1 (secretin family): these receptors have a large extracellular domain. The peptide binds in two steps: one end docks onto the extracellular domain, and the other end inserts into the helical core to switch the receptor on. Examples include receptors for glucagon, parathyroid hormone and calcitonin.
Switching on the signal
When the peptide binds, the receptor changes shape. It then activates a G protein inside the cell, which passes the message on:
| G protein | Main effect | Second messenger |
|---|---|---|
| Gs | Stimulates adenylyl cyclase | cAMP rises |
| Gi/o | Inhibits adenylyl cyclase | cAMP falls |
| Gq | Activates phospholipase C | Calcium released inside the cell |
A single receptor can activate many G proteins, and each of those triggers many second-messenger molecules. This amplification is why tiny hormone concentrations can have large effects.
Switching off: desensitisation
After activation, enzymes called GRKs tag the receptor with phosphate groups. This recruits β-arrestin, which blocks further G protein signalling and often pulls the receptor inside the cell (internalisation). This stops cells over-responding to a persistent signal.
Biased agonism
Different molecules binding the same receptor can favour different pathways, for example G protein signalling over β-arrestin recruitment. This biased agonism is an active research area, because it may make it possible to separate a receptor's beneficial effects from unwanted ones.
Measuring receptor activity in the lab
- Binding assays measure how tightly a peptide binds, reported as Kd or Ki.
- cAMP and calcium assays measure signalling and give a potency value (EC₅₀): the concentration that produces half the maximum response.
- BRET and FRET biosensors follow G protein and β-arrestin recruitment in living cells in real time.
- Cryo-electron microscopy shows what peptide–receptor–G protein complexes look like at near-atomic resolution.
Related articles
- A brief history of peptide science
- Peptide structure: from sequence to shape
- Peptides in nature: the body's messengers
Sources and further reading
- Hauser AS et al. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 2017;16:829–842. doi:10.1038/nrd.2017.178 · PMID: 29075003
- Rasmussen SGF et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 2011;477:549–555. doi:10.1038/nature10361 · PMID: 21772288
- The Nobel Prize in Chemistry 2012 (Lefkowitz, Kobilka). www.nobelprize.org/prizes/chemistry/2012/summary