Peptides rarely enter cells. Most are too large and too polar to cross a membrane, so they act from outside by binding receptors embedded in the cell surface. The receptor changes shape when the peptide binds, and that change is relayed to the inside of the cell as a chemical signal. Understanding this handoff is the key to reading peptide research: nearly every reported effect is, at its root, a receptor being switched on or off.
Lock and key, with a soft lock
The classic picture is a key (the peptide, or ligand) fitting a lock (the receptor). It is useful but too rigid. Real receptors are flexible, and binding is better described as induced fit: the ligand and the receptor adjust to one another, and the strength of the resulting complex is measured as affinity. Affinity is usually reported as a dissociation constant, Kd, or an inhibition constant, Ki; a lower number means tighter binding. Because it is so easy to misread, note that a peptide with high affinity is not necessarily a strong activator. Affinity describes how well it sticks, not what happens next.
G-protein-coupled receptors
The largest family of peptide receptors is the G-protein-coupled receptors (GPCRs), seven-helix proteins that thread back and forth through the membrane. When a peptide binds the outer face, the inner face recruits a G protein and swaps its bound GDP for GTP. The activated G protein then acts on effector enzymes: Gs raises cyclic AMP, Gi lowers it, and Gq raises intracellular calcium through phospholipase C. The GLP-1 receptor, the growth-hormone secretagogue receptor targeted by ipamorelin, and the melanocortin receptors studied with PT-141 and the melanotans are all GPCRs, which is why cyclic AMP and calcium assays appear so often in their literature.
Other receptor classes
Not every peptide works through a GPCR. Insulin and insulin-like growth factors bind receptor tyrosine kinases, which phosphorylate themselves and then a chain of intracellular proteins. Some peptides bind ion channels directly, changing the flow of sodium, calcium or potassium. Others, including several short fragments studied for tissue repair, are proposed to act on integrins or on extracellular matrix proteins rather than on a classical receptor at all, and the literature on those mechanisms is correspondingly less settled.
From receptor to response
A single activated receptor does not produce a single effect. It starts a cascade: second messengers such as cyclic AMP or calcium activate kinases, kinases phosphorylate transcription factors, and transcription factors change which genes are expressed. Each step amplifies the signal and opens branches, so one peptide can raise gene expression in one pathway while lowering it in another. This is why studies report several readouts, and why an effect seen in one cell type may not appear in another with a different set of downstream proteins.
Desensitisation and internalisation
Receptors are also switched off. After activation, GPCRs are phosphorylated and bound by arrestins, which both blocks further G-protein signalling and pulls the receptor into the cell for recycling or degradation. Continuous exposure to a ligand therefore tends to reduce the response over time, a process called desensitisation. Study designs that compare continuous with pulsed exposure, common in growth-hormone secretagogue research, exist because of this.
Reading the numbers
- EC50: the concentration producing half the maximal response in a functional assay. It reflects potency, which depends on affinity and on how efficiently binding is converted to signal.
- Emax: the maximal response. Two ligands can share an EC50 but differ in Emax; the one with the lower ceiling is a partial agonist.
- Selectivity: the ratio of a ligand's potency at its intended receptor to its potency at related receptors. A ten-fold ratio is modest; a thousand-fold ratio is what most tool compounds aim for.
- Biased agonism: some ligands favour G-protein signalling over arrestin recruitment, or the reverse, at the same receptor. Newer papers increasingly report both arms.
Key takeaways
- Peptides mostly act at cell-surface receptors; the receptor, not the peptide, produces the intracellular signal.
- GPCRs are the dominant peptide receptor family, signalling through cyclic AMP or calcium.
- Affinity, potency and efficacy are different measurements; a paper reporting one does not tell you the others.
- Desensitisation means dose schedule shapes the response, which is why pulsed and continuous exposure are compared.
