A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• The gamma-aminobutyric acid type B (GABA-B) receptor is crucial for synaptic inhibition in the central nervous system.
• Current treatments for CNS disorders targeting GABA-B receptors are limited, with only baclofen (an activator) available for spasticity.
• Developing inhibitors, particularly negative allosteric modulators (NAMs), presents therapeutic opportunities for conditions like absence seizures and cognitive dysfunction.

Purpose of the Study:

• To elucidate the mechanism of action of the novel GABA-B receptor NAM, CLH304a.
• To explore the potential for designing new NAMs based on CLH304a's structure.
• To identify the specific subunit and domain of the GABA-B receptor targeted by CLH304a.

Main Methods:

• Inhibition of native GABA-B receptor activity in cultured cerebellar granular neurons.
• Characterization of CLH304a's inverse agonist properties and non-competitive inhibition of agonists.
• Utilizing combinations of wild-type and mutated GB1 and GB2 subunits to determine the binding site.

Main Results:

• CLH304a effectively inhibits native GABA-B receptor activity.
• CLH304a acts as an inverse agonist, non-competitively inhibiting GABA's effect.
• CLH304a was found to target the heptahelical domain of the GB2 subunits of the GABA-B receptor.

Conclusions:

• CLH304a demonstrates inverse agonism and targets the GB2 subunit's heptahelical domain.
• The findings pave the way for designing novel GABA-B receptor NAMs.
• Targeting the GB2 subunit offers innovative therapeutic strategies for CNS disorders via GABA-B receptor inhibition.