Neurochemical Research, Vol. 25, No. 5, 2000, pp. 583–590 583 0364-3190/00/0500-0583$18.00/0 © 2000 Plenum Publishing Corporation The Neuronal Nicotinic Acetylcholine Receptor in Some Hereditary Epilepsies* F. J. Barrantes, 1,2 E. Aztiria, 1 M. B. Rauschemberger, 1 and A. Vasconsuelo 1 (Accepted February 28, 2000) Recent advances in human genetics and in the neurobiology of neurotransmitter receptors and channels have led to the discovery of specific genes associated with hereditary epileptic pheno- types. All the genes identified to date code for ligand- and voltage-gated ion channels. Some clinically rare idiopathic epilepsies are associated with mutations in genes coding for different neuronal nicotinic acetylcholine receptor (AChR) subunits. Distinct α subunits are found in the brain and in the peripheral nervous system, and structural, non-α subunits like β2 and β4 con- fer different properties to neuronal receptors. Thus, the final properties of the oligomeric AChR depend on the different combinations of α and β subunits. Most mutations found so far occur in the α4 chain, the most abundant subunit in the central nervous system. Specifically, the iden- tification of mutations in the α4 subunit of neuronal AChR in human benign familial neonatal convulsions (BFNC) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) raise the possibility that the observed gene defects are linked (causatively) with these two diseases or, alternatively, that AChR α4 mutants increase the probability of epileptic discharges. We dis- cuss testable hypotheses for unraveling the pathophysiology of these two disorders associated with AChR mutations. KEY WORDS: Epilepsy; neuronal pathology; brain; brain disorders; acetylcholine receptor; hereditary diseases. 1 Instituto de Investigaciones Bioquímicas de Bahía Blanca, B8000FWB Bahía Blanca, Argentina. 2 To whom to address reprint requests: Instituto de Investigaciones Bioquímicas, Universidad Nac. del Sur/CONICET, B8000FWB Bahía Blanca, Argentina. fax No. (054) 291 4861200; e-mail: rtfjb1@criba.edu.ar * Special issue in honor of Dr. Nicholas G. Bazan. neuronal nicotinic acetylcholine receptor (AChR). Mu- tations of this subunit were associated with autosomal dominant nocturnal frontal lobe epilepsy (2) and more recently with other epileptic disorders (3–7). The re- cent advances in our knowledge of neurotransmitter re- ceptors and channels paved the way for the discovery of other linkages between gene coding for specific channel proteins and epileptic disorders. Thus, it was possible to associate some forms of benign familial neonatal convulsions (BFNC) with mutations in two re- lated potassium channel genes, KCNQ2 and KCNQ3 (8–10). In addition, other ionotropic (11,12) and metabo- tropic (13) receptors could be related to other epileptic phenotypes. The Normal Neuronal AChR. The AChR is part of the superfamily of ligand-gated ion channels (LGIC). Members of the family of neuronal nicotinic AChR are INTRODUCTION Epileptic disorders affect about 0.5–2% of the world’s population. Although phenotypic epileptic characters have been established as signs of Mendelian inheritance in more than 100 human diseases, only a few specific genes have been causally linked to specific epileptic disorders (1). Until recently, the only gene coding for an ion channel that has been found to be re- lated to epilepsy in humans is the α4 subunit of the