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Volume 17, Number 23, Issue of December 1, 1997 pp. 9035-9047

Mutation Causing Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Alters Ca²⁺ Permeability, Conductance, and Gating of Human 42 Nicotinic Acetylcholine Receptors

Received July 7, 1997; revised Sept. 17, 1997; accepted Sept. 18, 1997.

Alexander Kuryatov, Volodymyr Gerzanich, Mark Nelson, Felix Olale, and Jon Lindstrom

Department of Neuroscience, Medical School, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6074

A mutation (S247F) in the channel-lining domain (M2) of the 4 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 42 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 42 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 42 AChRs. Addition of the 5 subunit restored Ca²⁺ permeability to the mutant 425 AChRs. At 80 mV, wild-type 42 AChR single channel currents exhibited two conductances, each with two mean open times (₁ = 17 pS, ₁ = 3.7 msec, and ₂ = 23.4 msec; ₂ = 28 pS, ₁ = 1.9 msec, and ₂ = 8.1 msec). In contrast, mutant AChRs exhibited only one conductance of 11 pS, with ₁ = 1.9 msec and ₂ = 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 5 subunit, the overall functionality of these AChRs could be maintained despite the mutation in the 4 subunit.

Key words: autosomal dominant nocturnal frontal lobe epilepsy; nicotinic acetylcholine receptors; calcium permeability; desensitization; epilepsy; single channel

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