Pore Structure of the Cys-loop Ligand-gated Ion Channels

Abstract

The Cys-loop receptor family of ligand-gated ion channels (LGICs) play a key role in synaptic transmission in the central nervous system of animals. Recent advances have led to the elucidation of two crystal structures of related prokaryotic LGICs and the electron micrograph derived structure of the acetylcholine receptor from Torpedo marmorata. Here, we review the structural and biochemical data that form our understanding of the structure of the channel pore. We introduce original data from the glycine receptor using the substituted-cysteine accessibility technique and show that while the helical structure of the segment that surrounds the channel pore is generally agreed, the location of the channel gate, the pore diameter and the structure that forms the entry to the channel pore are likely to differ between receptors. The fundamental structural differences between anion and cation selective receptors and how these differences are related to the pore structure are also considered.

Transmembrane Domain V Plays a Stabilizing Role in the Function of Human Bile Acid Transporter SLC10A2

“…20–22 Taking advantage of this chemistry, the MTSET reagent can be incubated with the cysteine mutants; then, the chemically-modified mutants can be assayed for transport function to identify residues that are in aqueous environments. In the TMs, these environments could signify a substrate pathway or in a binding pocket.…”

A prokaryotic perspective on pentameric ligand-gated ion channel structure

“…The pore shape of ELIC, GLIC and the Torpedo nAChR has been compared extensively by Absalom and colleagues [166] in the light of the recent structures, but also in the context of SCAM data. Before comparing the structures they point out the drawback that the differences in packing of the α1-and α3-helices to helix α2, which is tighter in ELIC and GLIC, might be due to the different methods used to determine the structures.…”

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).…”