Insights into channel function via channel dysfunction.

The nicotinic synapse has been a touchstone for advances in neuroscience ever since Jean Nicot, the French ambassador to Portugal, sent some tobacco seeds home to Paris in 1550 with a note that the New World plant had interesting effects when smoked. Now the muscle nicotinic acetylcholine receptor (nAChR) is a well-studied example of ligand-gated ion channels. After a motor neuron is stimulated, the nerve impulse reaches the presynaptic terminal, where it evokes release of acetylcholine (ACh) into the synapse. The nAChR depolarizes the postsynaptic muscle and triggers muscle action potentials; muscle contraction follows. To date, several nAChR subtypes have been successfully isolated, purified, imaged, and expressed, and unitary currents have been recorded from these channels (1). Researchers continue to unravel the molecular mechanisms of these macromolecules that are embedded in membranes at vertebrate nerve-muscle synapses, at invertebrate nicotinic synapses (which explains why nicotine-producing tobacco plants have a select advantage against invertebrate pests), and in the vertebrate central system (which explains Jean Nicot’s fascination with those leaves). However, the precise structural events that trigger channel opening or “gating” remain mostly unknown. Site-directed mutagenesis reveals some information about nAChR function but fails to give us an appreciation for the physiological significance of the receptor’s biophysical properties. During the last decade, the venerable pharmacological approaches have been aided by newer insights from molecular genetics. We now appreciate that a number of naturally occurring mutations within nAChRs lead to severe disorders. These ion-channel–associated disorders are collectively known as channelopathies. The nAChR is a heteropentamer assembled from α, β, γ, (or ε) and δ subunits (Figure 1). Each subunit is thought to contain a large N-terminal domain, followed by four transmembrane regions (M1–M4) with a large cytoplasmic loop between M3 and M4. In the central nervous system, at least five mutations linked to autosomal dominant nocturnal frontal lobe epilepsy lie within, or immediately adjacent to, M2 — the putative pore-forming region of neuronal nAChR subunits (2, 3). At the nerve-muscle synapse, at least 26 mutations in the extracellular, transmembrane, and cytoplasmic do-mains of the nAChR lead to different forms of congenital myasthenic syndrome (CMS) (4, 5). Thus these clinical cases aid in assigning physiological functions to the biophysical properties of nicotinic receptors. In this issue of the JCI, Shen and colleagues report the channel kinetics from a valine to leucine mutation (V132L) located in the α subunit of the muscle nAChR within the signature cystine loop (cys-loop) (6). The cys-loop is a highly conserved structure found in