Molecular modelling reveals how abundance of α4 sub-type in synaptic GABARA receptor can lead to refractoriness toward GABA and BZ-type drugs

Epilepsy is a complex neurological disorder with genetic and acquired causes, and the drugs presently used to treat epilepsy are not effective in about 30% of the cases. Identification of the molecular mechanisms of resistance will help in the development of newer molecules for treatment. Recent clinical data indicate increased expression of alpha 4- and gamma 2-containing synaptic GABARA receptors in patients of focal cortical dysplasia (FCD), which is associated with refractory epilepsy pathology. We have investigated, by molecular modelling and docking, the structure and ligand-binding efficiency of the alpha 4-containing hetero-pentameric synaptic GABARA receptor. Though the overall conformation is similar to that of the alpha 1-containing receptor, local conformational changes are seen due to differences between aligned alpha 1 and alpha 4 sub-type residues. The overlaps ALA209(alpha 1)/PRO215(alpha 4) and PHE73(alpha 1)/TYR79(alpha 4) have together caused conformational changes in ARG100(alpha 4) (aligned with ARG94 in alpha 1) thereby affecting key hydrogen bonding interactions with the inhibitory neurotransmitter GABA. This may influence the nature of seizures as strength of GABA-binding is known to affect the nature of Inhibitory Post-Synaptic Currents (IPSCs) from GABAergic neurons. The residue ARG135 (alpha 4) aligns with the residue HIS129 (alpha 1) in the benzodiazapine binding pocket. Molecular modelling also shows that a steric clash between benzodiazapine-type (BZ-type) drugs and ARG135 would reduce the binding of BZ-type drugs to alpha 4-containing receptor. These two findings rationalize the observed association between over-expression of alpha 4-containing synaptic GABARA receptors and refractory epilepsy pathology in FCD. The accurate three-dimensional geometry of the receptor-drug complex made available by these modelling studies will help in designing effective drugs.

Automated summary

Epilepsy is a complex neurological disorder and the current drugs used for treatment are ineffective in some cases. Recent studies have found increased expression of alpha 4- and gamma 2-containing synaptic GABARA receptors in patients with refractory epilepsy pathology. Molecular modelling and docking techniques have revealed differences in the structure and ligand-binding efficiency of the alpha 4-containing receptor compared to the alpha 1-containing receptor. These differences may affect the binding of the inhibitory neurotransmitter GABA and the nature of seizures. Furthermore, a steric clash between a specific amino acid residue in the alpha 4-containing receptor and benzodiazapine-type drugs may reduce their binding. These findings provide insights for the development of more effective drugs for epilepsy.