Nicotinic acetylcholine receptors (nAChRs) are integral membrane proteins and prototypic members of the ligand-gated ion-channel superfamily, which has precursors in the prokaryotic world. They are formed by the assembly of five transmembrane subunits, selected from a pool of 17 homologous polypeptides (a1-10, b1-4, c, d, and e). There are many nAChR subtypes, each consisting of a specific combination of subunits, which mediate diverse physiological functions. They are widely expressed in the central nervous system, while, in the periphery, they mediate synaptic transmission at the neuromuscular junction and ganglia. nAChRs are also found in non-neuronal ⁄ nonmuscle cells (keratinocytes, epithelia, macrophages, etc.). Extensive research has determined the specific function of several nAChR subtypes. nAChRs are now important therapeutic targets for various diseases, including myasthenia gravis, Alzheimer's and Parkinson's diseases, and schizophrenia, as well as for the cessation of smoking. However, knowledge is still incomplete, largely because of a lack of high-resolution X-ray structures for these molecules. Nevertheless, electron microscopy studies on 2D crystals of nAChR from fish electric organs and the determination of the high-resolution X-ray structure of the acetylcholine binding protein (AChBP) from snails, a homolog of the extracellular domain of the nAChR, have been major steps forward and the data obtained have important implications for the design of subtype-specific drugs. Here, we review some of the latest advances in our understanding of nAChRs and their involvement in physiology and pathology.

In the autoimmune disease myasthenia gravis (MG), antibodies against the muscle nicotinic acetylcholine receptor (AChR) cause loss of functional AChR in the neuromuscular junction. To isolate AChR‐specific human antibody fragments (Fab), a phage‐display library was constructed from an MG patient's thymic B lymphocytes. The first Fab isolated had a low affinity for human AChR, but two sequential antibody chain shufflings using the MG donor heavy and light chain gene repertoires resulted in isolating two new Fab with an approximately 30‐fold higher binding ability. The selected Fab contained extensively mutated heavy and light chains and probably represent intraclonal variants of a common progenitor having diverged in vivo by somatic hypermutation. Interestingly, the isolated Fab bound to an extracellular highly immunogenic region located either on an α‐subunit site affected by the γ/ϵ‐subunits or on the interface between α‐ and γ/ϵ‐subunits. This region is not the previously described "main immunogenic region" (MIR), although it seems to be close to it, as one improved Fab and an anti‐MIR mAb competed for AChR binding with distinctly different subpopulations of MG sera. Furthermore, this Fab protected surface AChR in cell cultures against MG autoantibody‐induced antigenic modulation, suggesting a potential therapeutic use in MG, especially in combination with a human anti‐MIR Fab.

Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR).

Myasthenia gravis (MG) is a T-cell dependent autoimmune disease mediated by autoantibodies, which mainly target muscle nicotinic acetylcholine receptors (AChR) and cause loss of functional AChRs in the neuromuscular junction. Both MG and its major autoantigen are studied extensively, yet the etiology of the disease remains unclear, although it is known to be associated with the thymus. A genetic predisposition, combined with several unidentified environmental stimuli, likely creates a favorable milieu in which the disease can appear. Current research focusses on elucidating the cellular and molecular pathways of immune dysregulation, which underly MG outburst and progression. Considerable progress has been made concerning the involvement of the thymus, the identification of impaired mechanisms of immune control and the B–T-cell interaction in MG pathogenesis, while the role of chemokines arises as an intriguing new puzzle. Recent findings fueled the development of novel therapeutic approaches with some encouraging, although preliminary, results. This review summarizes recent achievements in the fields of both basic research and therapeutics.

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