Response to different ligands

Response to different ligands

With this example of the GABA receptor the concept of different ligands and their responses at one single receptor with multiple binding pockets can be explained.

The GABA-R is an ion channel with a binding site for GABA and additional ‘modulatory’ sites.

In case the endogenous ligand GABA binds, the ion channel opens a little allowing some chloride ions to enter the cell. This causes a minor hyperpolarisation at the post-synaptic cell (which then cannot be excitated).

The GABA-R has additional binding pockets, either for an extra GABA molecule or another modulatory molecule than GABA. Binding of GABA plus an additional modulatory agonist (e.g. diazepam, phenobarbital) results in a higher response than GABA alone.

Addition of an antagonist at the modulatory binding pocket will bring the membrane potential back to the level similar to that when 1 GABA was bound to the receptor. The inverse agonist depolarises the membrane by completely closing the ion channel.