coagonist

A coagonist is a ligand that binds to a receptor at a site distinct from the primary agonist binding site and modulates receptor activation. In many systems, a coagonist is required in addition to the main agonist to achieve full receptor activation, or it enhances the receptor’s response.

The best-known example is the NMDA-type glutamate receptor. For activation, glutamate binding to the NR2 subunit must be accompanied by binding of a coagonist, typically glycine or D-serine, to the obligatory glycine-binding site on the NR1 subunit. Without a coagonist, NMDA channels show little current even when glutamate is present; with both ligands, the receptor opens and allows calcium and other cations to flow, contributing to synaptic plasticity. The occupancy of the coagonist site can be regulated by transporters and enzymes, and local levels of glycine and D-serine influence NMDA receptor function.

Coagonist action is not limited to NMDA receptors. Other receptors may similarly require or be modulated by a second ligand at an allosteric site, which can enhance or enable maximal responses. Pharmacological agents can also act as coagonists or allosteric modulators, altering receptor sensitivity or efficacy without directly competing with the primary agonist.

Clinical relevance includes the idea that altering coagonist availability or affinity can modify receptor activity in neurological and psychiatric disorders. For example, strategies that increase glycine site occupancy have been explored to enhance NMDA receptor function in schizophrenia, while excessive coagonist activity may contribute to excitotoxic risks in CNS injury. See also allosteric modulation and ligand-gated ion channels.