Recent advances in understanding the structure of nicotinic acetylcholine receptors

Abstract

SummaryNicotinic acetylcholine receptors (nAChRs), members of the Cys-loop ligand-gated ion channels (LGICs) superfamily, are involved in signal transduction upon binding of the neurotransmitter acetylcholine or exogenous ligands, such as nicotine. nAChRs are pentameric assemblies of homologous subunits surrounding a central pore that gates cation flux, and are expressed at the neuromuscular junction and in the nervous system and several nonneuronal cell types. The 17 known nAChR subunits assemble into a variety of pharmacologically distinct receptor subtypes. nAChRs are implicated in a range of physiological functions and pathophysiological conditions related to muscle contraction, learning and memory, reward, motor control, arousal, and analgesia, and therefore present an important target for drug research. Such studies would be greatly facilitated by knowledge of the high-resolution structure of the nAChR. Although this information is far from complete, important progress has been made mainly based on electron microscopy studies of Torpedo nAChR and the high-resolution X-ray crystal structures of the homologous molluscan acetylcholine-binding proteins, the extracellular domain of the mouse nAChR a1 subunit, and two prokaryotic pentameric LGICs. Here, we review some of the latest advances in our understanding of nAChR structure and gating.

MmTX1 and MmTX2 from coral snake venom potently modulate GABA A receptor activity

“…Subunit. Accumulating evidence obtained from nAChRs establishes a vital role for loop-C within the α subunit in determining receptor sensitivity to α-neurotoxins (57,58). Subsequently, we hypothesized that sMmTX1 interacts with the corresponding region in the α1 subunit of GABA A receptors expressed in oocytes (Figs.…”

Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations

“…These protein complexes are widely expressed in muscle and neuronal tissues, and their potential utility as drug targets for various therapeutic interventions has been increasingly recognized in recent years (Aubin et al, 2011;Wallace and Porter, 2011;Williams et al, 2011). Heteromeric nAChRs are composed of ␣ and ␤ subunits, which assemble around and operate a central, cation-conducting pore domain (Keramidas et al, 2004;Absalom et al, 2009;Zouridakis et al, 2009). Muscle-type nAChRs, including their subunit stoichiometry and role as postsynaptic ACh receptors at the neuromuscular junction (Changeux, 2010a), are well understood.…”

“…Aside from homomerictype ␣7 or ␣8 nAChRs, there are three neuronal ␤ subunits (␤2-␤4) and at least seven neuronal ␣ subunits (␣2-␣6, ␣9, ␣10) that assemble to form heteromeric nAChR pentamers (Keramidas et al, 2004;Dani and Bertrand, 2007;Absalom et al, 2009;Zouridakis et al, 2009). Each of these subunits is expressed in multiple brain areas, often with specific subcellular localization and developmental expression patterns (Marks et al, 1992;Azam et al, 2002).…”

Directed Mutagenesis of Nicotinic Receptors to Investigate Receptor Function

“…Seventeen homologous subunits (1 -10, 1 -4, ,  and ) are known in vertebrates (Zouridakis et al, 2009). This pool of subunits accounts for the vast number of nACh receptor subtypes that exhibit extensive functional diversity with respect to their pharmacological profile, spatiotemporal expression patterns and kinetic properties.…”