Why Drugs Sometimes Cause Receptor Potentiation Rather Than Inhibition

Summary: Receptor potentiation was observed when the antagonists bind to receptors that consist of different subunits, where it acts as a subunit.

Source: RUB

Professor Andreas Reiner and Stefan Pollok from the junior research group Cellular Neurobiology at Ruhr-Universität Bochum (RUB) report on this unexpected finding and the underlying mechanisms in the journal PNAS from 30 September 2020.

Wanted: more precise drugs

Glutamate is the messenger substance, which the brain uses to pass on excitatory signals. Receptors for this neurotransmitter are a promising target for drug development, as they are involved in many pathological processes. For example, they play a role in epilepsy, mental disorders, strokes or brain tumours.

“In these cases, it may be beneficial to reduce the activity of glutamate receptors,” explains Andreas Reiner.

For this purpose, so-called antagonists have been developed, i.e. drugs that inhibit the activation of glutamate receptors. However, many of these antagonists inhibit all glutamate receptor subtypes, thus producing undesired adverse effects. To circumvent this problem, researchers are currently looking for drugs that only bind to certain receptor subtypes.

Measuring the effects of antagonists directly

In their current study, the researchers analysed the effects of such antagonists on selected receptor subtypes in more detail. For this purpose, they used cultivated cells containing only individual subtypes or specific receptor combinations. Using a dedicated application technique and electrophysiological measurements, the researchers rapidly activated the glutamate receptors, similar to their activation at synapses in the brain, and measured the influence of the antagonists.

Potentiation instead of inhibition

“We made a surprising observation in the process,” says Stefan Pollok. “For certain receptor combinations, we did indeed see a reduction in activation, as expected, but, at the same time, the natural inactivation process was reduced or even completely abolished.” The result was a longer-lasting and overall stronger response than without the antagonist. Instead of the desired inhibition, the researchers observed a potentiating effect.

This shows a patch clamp
Using a dedicated application technique and electrophysiological measurements, the researchers rapidly activated the glutamate receptors. The picture shows a setup for patch-clamp electrophysiology. Image is credited to RUB, Marquard.

In subsequent experiments, the team identified the molecular mechanisms of this behaviour more precisely: The potentiating effect is observed when the antagonists bind to receptors that consist of different subunits where it acts on only a part of the subunits.

“Such so-called heteromeric receptors are, however, of great importance for signal transduction in the central nervous system,” says Andreas Reiner.

The findings are therefore significant for neuroscientists, who are increasingly using selective antagonists to decipher the function of the various receptor subtypes. On the other hand, the study might also have an impact on the development of new therapeutics.

“We’ve gained new insights into how this fascinating class of receptors works,” concludes Andreas Reiner. In the future, he also wants to investigate the effects of other glutamate receptor drugs.

About this neuroscience research article

Garvan Institute of Medical Research
Andreas Reiner – RUB
Image Source:
The image is credited to RUB, Marquard.

Original Research: Open access
“Subunit-selective iGluR antagonists can potentiate heteromeric receptor responses by blocking desensitization” by Stefan Pollok and Andreas Reiner. PNAS.


Subunit-selective iGluR antagonists can potentiate heteromeric receptor responses by blocking desensitization

Ionotropic glutamate receptors (iGluRs) are key molecules for synaptic signaling in the central nervous system, which makes them promising drug targets. Intensive efforts are being devoted to the development of subunit-selective ligands, which should enable more precise pharmacologic interventions while limiting the effects on overall neuronal circuit function. However, many AMPA and kainate receptor complexes in vivo are heteromers composed of different subunits. Despite their importance, little is known about how subunit-selective ligands affect the gating of heteromeric iGluRs, namely their activation and desensitization properties. Using fast ligand application experiments, we studied the effects of competitive antagonists that block glutamate from binding at part of the four subunits. We found that UBP-310, a kainate receptor antagonist with high selectivity for GluK1 subunits, reduces the desensitization of GluK1/GluK2 heteromers and fully abolishes the desensitization of GluK1/GluK5 heteromers. This effect is mirrored by subunit-selective agonists and heteromeric receptors that contain binding-impaired subunits, as we show for both kainate and GluA2 AMPA receptors. These findings are consistent with a model in which incomplete agonist occupancy at the four receptor subunits can provide activation without inducing desensitization. However, we did not detect significant steady-state currents during UBP-310 dissociation from GluK1 homotetramers, indicating that antagonist dissociation proceeds in a nonuniform and cooperativity-driven manner, which disfavors nondesensitizing occupancy states. Besides providing mechanistic insights, these results have direct implications for the use of subunit-selective antagonists in neuroscience research and envisioned therapeutic interventions.

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