Ion channels and epilepsy

Abstract

In order for cells to retain their integrity to water and yet permeate charged ions, the phospholipid cell membrane contains transmembrane proteins that allow the passage of specific ions from the interior of the cell to outside, and vice versa. There is a huge diversity of these ion channels. Some are tissue-specific; others are widely distributed throughout the body. They contribute to the maintenance of the negative resting membrane potential inside cells. Unsurprisingly, these membrane channels are integral to the processes of electrical signalling and excitation that are central to the functioning of the nervous system. Figure 1a shows a generic ion channel. Figure 1. ( A ) Diagrammatic representation of a voltage-gated ion channel α subunit. This could be a sodium or calcium channel. Note the four homologous repeats (I–IV), each with six transmembrane domains (1–6). The fourth transmembrane domain (4) has positively charged segments and acts as the voltage sensor. ( B ) Diagrammatic representation of an assembled calcium channel with auxiliary (β, α2δ and γ) subunits. The four homologous repeats (I–IV) are marked on the α1 subunit, and come together to make the channel pore. The assembly of sodium channels is similar, but only has auxiliary β subunits. The past 15 years have seen rapid expansion in the discovery of disease-causing mutations in genes encoding ion channel proteins. These manifest as neurological, cardiac, renal and respiratory disorders, the most common being cystic fibrosis. This disparate collection of syndromes is now referred to as the channelopathies, a descriptive term referring to the common underlying pathophysiology of ion channel dysfunction. Ion channels themselves are divided into two broad categories, depending on their mode of activation. Voltage-gated channels are controlled by changes in membrane potential, ligand-gated channels by ligand binding (Table 1). View this table: Table 1 Ion channels implicated in epilepsy Epilepsy affects up to … Address correspondence to Dr T.D. Graves, Department of Molecular Neurosciences, Institute of Neurology, University College London, Queen Square, London WC1N 3BG. email: t.graves{at}ion.ucl.ac.uk