Gating of Pentameric Ligand-Gated Ion Channels: Structural Insights and Ambiguities

Abstract

Pentameric ligand-gated ion channels (pLGICs) mediate fast synaptic communication by converting chemical signals into an electrical response. Recently solved agonist-bound and agonist-free structures greatly extend our understanding of these complex molecular machines. A key challenge to a full description of function, however, is the ability to unequivocally relate determined structures to the canonical resting, open, and desensitized states. Here, we review current understanding of pLGIC structure, with a focus on the conformational changes underlying channel gating. We compare available structural information and review the evidence supporting the assignment of each structure to a particular conformational state. We discuss multiple factors that may complicate the interpretation of crystal structures, highlighting the potential influence of lipids and detergents. We contend that further advances in the structural biology of pLGICs will require deeper insight into the nature of pLGIC-lipid interactions.

Intramembrane Aromatic Interactions Influence the Lipid Sensitivities of Pentameric Ligand-gated Ion Channels

“…Significantly, agonist binding does not lead to a widening of the channel pore in ELIC, even with mutants that show no propensity to undergo desensitization (54,55). Although wild type ELIC appears less sensitive to detergent than the nAChR, the absence of aromatic residues in the post-M4 region may weaken post-M4-M1/M3 interactions so that detergent solubilization leads to a non-functional conformation (15), as does reconstitution into the minimal PC membranes.…”

“…Lipid-dependent mechanisms for "awakening" uncoupled nAChRs have been identified and could play a role modulating synaptic communication (14). The lipid-dependent uncoupled conformation may also be germane to the interpretation of crystal structures of detergent-solubilized pLGICs (15). Lipids may exert their effects on nAChR function by interacting with interstitial sites between ␣-helices in the transmembrane domain (16,17) or by interacting with the lipid-protein interface (11,16,18,19).…”

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

“…Several factors may contribute to the observed structural differences between these channels (17,61). The structural models of nAChR in the unliganded and liganded conformations are based on 4-and 6-Å resolution data, respectively (1,62).…”

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

“…In fact, no movement of the porelining M2 α-helices was detected with mutants that prolong channel opening and exhibit no propensity to desensitize. It has been suggested that the ELIC structures reflect a conformation that is refractory to agonist binding [121] -i.e., a conformation that is functionally equivalent to the lipid-dependent uncoupled state of the Torpedo nAChR [122]. Significantly, the ELIC structures exhibit multiple proposed features of the uncoupled nAChR ( Figs.…”