Figure 8.

Schematic of Mechanisms in which Hyperekplexic Mutant GlyRs Disrupt Inhibitory Neurotransmission by Interacting with Pre- and Extra-synaptic GABA_ARs

(A) Under normal conditions, presynaptic GABA_ARs facilitate GABA release from GABAergic neuron terminals, activating postsynaptic GABA_ARs to inhibit neurons in the brainstem hypoglossal nucleus. The extra-synaptic GABA_ARs mediate the chronic inhibition of postsynaptic neurons in the brainstem hypoglossal nucleus.

(B) In hyperekplexia disease, the mutant GlyRα₁ binds to pre- and extra-synaptic GABA_ARs and, therefore, reduce GABA release and the chronic inhibition. The postsynaptic GlyRβ subunits prevent the mutant GlyRα₁ from binding to the GABA_ARs.

(C) DIA exerts its therapeutic effect by allosterically potentiating pre- and extra-synaptic α₅-containing GABA_ARs in the brainstem hypoglossal nucleus.