RT Journal Article SR Electronic T1 Mutation Causing Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Alters Ca2+ Permeability, Conductance, and Gating of Human α4β2 Nicotinic Acetylcholine Receptors JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 9035 OP 9047 DO 10.1523/JNEUROSCI.17-23-09035.1997 VO 17 IS 23 A1 Kuryatov, Alexander A1 Gerzanich, Volodymyr A1 Nelson, Mark A1 Olale, Felix A1 Lindstrom, Jon YR 1997 UL http://www.jneurosci.org/content/17/23/9035.abstract AB A mutation (S247F) in the channel-lining domain (M2) of the α4 nicotinic acetylcholine receptor (AChR) subunit has previously been linked genetically to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).To better understand the functional significance of this mutation, we characterized the properties of mutant and wild-type human α4β2 AChRs expressed in Xenopus oocytes. Both had similar expression levels and EC50 values for ACh and nicotine. Substantial use-dependent functional upregulation was found for mutant α4β2 AChRs, but not for wild type. Mutant AChR responses showed faster desensitization, slower recovery from desensitization, less inward rectification, and virtually no Ca2+permeability as compared with wild-type α4β2 AChRs. Addition of the α5 subunit restored Ca2+ permeability to the mutant α4β2α5 AChRs. At −80 mV, wild-type α4β2 AChR single channel currents exhibited two conductances, each with two mean open times (γ1 = 17 pS, τ1 = 3.7 msec, and τ2 = 23.4 msec; γ2 = 28 pS, τ1 = 1.9 msec, and τ2 = 8.1 msec). In contrast, mutant AChRs exhibited only one conductance of 11 pS, with τ1 = 1.9 msec and τ2 = 4.1 msec.The net effect of the mutation is to reduce AChR function. This could result in the hyperexcitability characteristic of epilepsy if the mutant AChRs were part of an inhibitory circuit, e.g., presynaptically regulating the release of GABA. In the minority of AChRs containing the α5 subunit, the overall functionality of these AChRs could be maintained despite the mutation in the α4 subunit.