Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy.
1. The normal and a mutant (S248F) human neuronal alpha4beta2 nicotinic receptors, and their interaction with the channel blocker carbamazepine (CBZ) have been modelled. The mutant, responsible for the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), has an enhanced sensitivity to and a slower recovery from desensitization, a lower conductance, short open times, reduced calcium permeability, and is 3 fold more sensitive to CBZ, a drug used in the treatment of partial epilepsies. 2. Mutant channel properties are explained by the physicochemical properties of the two Phe248 side chains, including size and cation-pi interaction, and their dynamic behaviour. A defective mechanism of dehydration might be responsible for the reduced calcium influx. 3. Phe248 residues are the main component of CBZ binding sites in the mutant, while this is not true for Ser248 in the normal receptor. 4. A higher number of blocking binding sites and a predicted higher affinity found for CBZ in the mutant account for its differential sensitivity to CBZ. 5. Aromatic-aromatic interactions between CBZ and the two Phe248 account for the difference in affinity, which is at least 12 times higher for the mutant, depending on the method used for calculating K(i). 6. Normal vs mutant differences in K(i), enhanced by the higher number of blocking binding sites in the mutant, seem excessive compared to the differential sensitivities to CBZ experimentally found. The negative cooperativity suggested by a predicted overlapping of blocking and non-blocking binding sites gives an explanation, as overlapping is higher in the mutant. 7. For both types of receptors we found that the carbamyl group of the best blocking conformers of CBZ forms hydrogen bonds with serine residues, which may explain the fundamental role of that moiety for this molecule to act as antiepileptic drug.
Ortells
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Instituto de Neurociencia (UBA-CONICET), Fac. de Cs. Ex. y Nat, Cdad. Univ, Pab 2, 4to Piso, Lab 54, 1428 Buenos Aires, Argentina. ortells@ail.retina.ar
Barrantes
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D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism; D002220:Carbamazepine / Q000737:chemistry* / Q000378:metabolism; D017034:Epilepsy, Frontal Lobe / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D000927:Anticonvulsants; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D002220:Carbamazepine