A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor.

Synaptic receptors respond to neurotransmitters by opening an ion channel across the post-synaptic membrane to elicit a cellular response. Here we use recent Torpedo acetylcholine receptor structures and functional measurements to delineate a key feature underlying allosteric communication between the agonist-binding extracellular and channel-gating transmembrane domains. Extensive mutagenesis at this inter-domain interface re-affirms a critical energetically coupled role for the principal α subunit β1-β2 and M2-M3 loops, with agonist binding re-positioning a key β1-β2 glutamate/valine to facilitate the outward motions of a conserved M2-M3 proline to open the channel gate.

Origin of acetylcholine antagonism in ELIC, a bacterial pentameric ligand-gated ion channel.

ELIC is a prokaryotic homopentameric ligand-gated ion channel that is homologous to vertebrate nicotinic acetylcholine receptors. Acetylcholine binds to ELIC but fails to activate it, despite bringing about conformational changes indicative of activation. Instead, acetylcholine competitively inhibits agonist-activated ELIC currents.

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels.

Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs.

Distinct functional roles for the M4 α-helix from each homologous subunit in the heteropentameric ligand-gated ion channel nAChR.

The outermost lipid-exposed α-helix (M4) in each of the homologous α, β, δ, and γ/ε subunits of the muscle nicotinic acetylcholine receptor (nAChR) has previously been proposed to act as a lipid sensor. However, the mechanism by which this sensor would function is not clear. To explore how the M4 α-helix from each subunit in human adult muscle nAChR influences function, and thus explore its putative role in lipid sensing, we functionally characterized alanine mutations at every residue in αM4, βM4, δM4, and εM4, along with both alanine and deletion mutations in the post-M4 region of each subunit.

Conformational transitions and ligand-binding to a muscle-type nicotinic acetylcholine receptor.

Fast synaptic communication requires receptors that respond to the presence of neurotransmitter by opening an ion channel across the post-synaptic membrane. The muscle-type nicotinic acetylcholine receptor from the electric fish, Torpedo, is the prototypic ligand-gated ion channel, yet the structural changes underlying channel activation remain undefined. Here we use cryo-EM to solve apo and agonist-bound structures of the Torpedo nicotinic receptor embedded in a lipid nanodisc.

Ion channels as lipid sensors: from structures to mechanisms.

Ion channels play critical roles in cellular function by facilitating the flow of ions across the membrane in response to chemical or mechanical stimuli. Ion channels operate in a lipid bilayer, which can modulate or define their function. Recent technical advancements have led to the solution of numerous ion channel structures solubilized in detergent and/or reconstituted into lipid bilayers, thus providing unprecedented insight into the mechanisms underlying ion channel-lipid interactions.

The functional role of the αM4 transmembrane helix in the muscle nicotinic acetylcholine receptor probed through mutagenesis and coevolutionary analyses.

The activity of the muscle-type nicotinic acetylcholine receptor (nAChR) is highly sensitive to lipids, but the underlying mechanisms remain poorly understood. The nAChR transmembrane α-helix, M4, is positioned at the perimeter of each subunit in direct contact with lipids and likely plays a central role in lipid sensing. To gain insight into the mechanisms underlying nAChR lipid sensing, we used homology modeling, coevolutionary analyses, site-directed mutagenesis, and electrophysiology to examine the role of the α-subunit M4 (αM4) in the function of the adult muscle nAChR.

Structural basis for the modulation of pentameric ligand-gated ion channel function by lipids.

Pentameric ligand-gated ion channels (pLGICs) play a central role in synaptic communication and are implicated in a plethora of neurological disorders leading to human disease. Membrane lipids are known to modulate pLGIC function, but the mechanisms underlying their effects are poorly understood. Recent structures reveal sites for the binding of membrane lipids to pLGICs, thus providing a structural basis for interpreting functional data on pLGIC-lipid interactions.

Light up and see: enhancement of the visual mismatch negativity (vMMN) by nicotine.

Both smoking and nicotine can facilitate cognitive efficiency in humans, however the exact mechanism underlying this improvement in cognitive performance is unclear. Nicotine-related improvements in visual task performance may stem from facilitation of the identification and encoding of rare deviant stimuli at early sensory levels. Visual processes at these early levels are thought to be indexed by the visual mismatch negativity (vMMN), an event-related potential (ERP) measure of pre-conscious deviant detection.

Nicotine and attention: event-related potential investigations in nonsmokers.

Research into the effects of nicotine and smoking on cognition has largely confirmed the subjective reports of smoking in smokers on mental functions, showing smoking abstinence to disrupt and smoking/nicotine to restore cognitive functioning. Evidence of performance improvements in nonsmokers has provided partial support for the absolute effects of nicotine on cognitive processes, which are independent of withdrawal relief, but the mechanisms underlying its pro-cognitive properties still remain elusive. The attentional facilitation frequently reported with smoking/nicotine may be indirectly related to its diffuse arousal-enhancing actions, as evidenced by electroencephalographic (EEG) fast frequency power increments, or it may reflect nicotine's direct modulating effects on specific neural processes governing stimulus encoding, selection and rejection.