Receptors and signalling: a short primer for peptide research

Two receptor families dominate

Most peptide targets fall into two structural classes. G-protein-coupled receptors are seven-transmembrane proteins that, on ligand binding, activate heterotrimeric G proteins; the class B subfamily to which GLP-1, GIP, GHRH and VIP receptors belong is characterised by a large extracellular domain that captures the peptide N-terminus. Receptor tyrosine kinases, such as the IGF-1 receptor, instead dimerise and autophosphorylate on ligand binding, initiating intracellular cascades directly.

Which family a target belongs to predicts the assay. GPCR work is usually read out as cAMP accumulation or calcium mobilisation; receptor tyrosine kinase work is read out as phosphorylation state by western blot or phospho-specific immunoassay.

Agonist vocabulary

A full agonist produces the maximal response the receptor system can generate. A partial agonist binds and activates but plateaus below that maximum, and in the presence of a full agonist can act functionally as an antagonist. An inverse agonist suppresses constitutive activity below baseline. An allosteric modulator binds away from the orthosteric site and changes the response to the natural ligand rather than producing one itself.

Potency and efficacy are distinct and frequently conflated. Potency is the concentration required for half-maximal effect, reported as EC50. Efficacy is the size of the maximal effect. A compound can be far more potent than a comparator while producing a smaller maximal response.

Biased signalling

A single receptor can couple to multiple downstream pathways — classically G-protein signalling and beta-arrestin recruitment. Ligands that preferentially engage one over the other are described as biased. Bias matters experimentally because two agonists with matched cAMP potency can produce entirely different receptor internalisation and desensitisation behaviour, and therefore different responses over long incubations.

Half-life engineering

Much of modern peptide design is not about receptor binding at all but about clearance. Lipidation, albumin-binding linkers, pegylation and protease-resistant substitutions all extend residence time without changing the receptor interaction. When comparing analogs, it is worth separating what a modification does to affinity from what it does to exposure — they are independent variables and are frequently confused in the secondary literature.