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Review
. 2012 Dec 9:2012:262941.
doi: 10.5402/2012/262941. eCollection 2012.

Neuronal nicotinic receptors in sleep-related epilepsy: studies in integrative biology

Andrea Becchetti  1
Affiliations
Review

Neuronal nicotinic receptors in sleep-related epilepsy: studies in integrative biology

Andrea Becchetti. ISRN Biochem. .

Abstract

Although Mendelian diseases are rare, when considered one by one, overall they constitute a significant social burden. Besides the medical aspects, they propose us one of the most general biological problems. Given the simplest physiological perturbation of an organism, that is, a single gene mutation, how do its effects percolate through the hierarchical biological levels to determine the pathogenesis? And how robust is the physiological system to this perturbation? To solve these problems, the study of genetic epilepsies caused by mutant ion channels presents special advantages, as it can exploit the full range of modern experimental methods. These allow to extend the functional analysis from single channels to whole brains. An instructive example is autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), which can be caused by mutations in neuronal nicotinic acetylcholine receptors. In vitro, such mutations often produce hyperfunctional receptors, at least in heterozygous condition. However, understanding how this leads to sleep-related frontal epilepsy is all but straightforward. Several available animal models are helping us to determine the effects of ADNFLE mutations on the mammalian brain. Because of the complexity of the cholinergic regulation in both developing and mature brains, several pathogenic mechanisms are possible, which also present different therapeutic implications.

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Figures

Figure 1
Figure 1
Schematic of the location of ADNFLE mutations within the nAChR subunit structure. (a) overall topology of the typical nAChR subunit; asterisks mark the location of the mutations listed in Table 2. Double arrows mark the probable transduction pathway between the ligand-binding pocket and the M2 segment, which constitutes at the same time the channel gate and the selectivity filter. The panel also shows the location of the Cys-loop and the Cys pair that defines the α subunits. The M3-M4 variable linker is implicated in channel interaction with the cytoskeleton and regulation by phosphorylation. (b) probable arrangement of the M1–M4 segments of the five subunits constituting the pentameric receptor. The M2 segments line the channel pore. On agonist binding, the ligand pocket partially rotates. Such conformational change is transferred to the M2 segments, whose rotation removes from the channel lumen several hydrophobic amino acid side chains. In this way, the pore diameter widens from about 0.3 nm to approximately 0.8 nm. This enlargement is accompanied by the movement of hydrophilic groups into the lumen. The overall effect is considerable increase in ion permeability. For introduction to the structure-function studies on nAChRs, see [7, 8, 12, 14, 15].
Figure 2
Figure 2
Simplified scheme of the ascending modulatory systems in the brain. The picture recapitulates the main ascending modulatory systems, with no pretension of neuroanatomical precision. Black (ACh): pontomesencephalic and basal forebrain cholinergic nuclei; light blue (GABA): GABAergic nuclei in the forebrain; brown: several noradrenergic (the main being locus coeruleus), dopaminergic, and serotonergic nuclei which cooperate in regulating the brain active states (see the main text); gray: hypothalamic histaminergic cells, which also regulate cortical activation. For clarity no connection pattern is shown for histaminergic, serotonergic, and dopaminergic nuclei. NE: norepinephrine.
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