Abstract
Rapid communication at the chemical synapse depends on the action of ion channels residing in the postsynaptic membrane. The channels open transiently upon the binding of a neurotransmitter released from the presynaptic nerve terminal, eliciting an electrical response. Membrane lipids also play a vital but poorly understood role in this process of synaptic transmission. The present study examines the lipid distribution around nicotinic acetylcholine (ACh) receptors in tubular vesicles made from postsynaptic membranes of the Torpedo ray, taking advantage of the recent advances in cryo-EM. A segregated distribution of lipid molecules is found in the outer leaflet of the bilayer. Apparent cholesterol-rich patches are located in specific annular regions next to the transmembrane helices and also in a more extended 'microdomain' between the apposed δ subunits of neighbouring receptors. The particular lipid distribution can be interpreted straightforwardly in relation to the gating movements revealed by an earlier time-resolved cryo-EM study, in which the membranes were exposed briefly to ACh. The results suggest that in addition to stabilizing the protein, cholesterol may play a mechanical role by conferring local rigidity to the membrane so that there is productive coupling between the extracellular and membrane domains, leading to opening of the channel.
Highlights
Rapid communication in the nervous system takes place by synaptic transmission, a process in which a neurotransmitter released from a nerve terminal binds transiently to ion channels located in the oppositely facing postsynaptic membrane of the target cell, stimulating the channels to open and effecting a change in membrane potential
Architecture of a tubular vesicle rely on the averaging of equatorial Fourier terms affected by the edges of the boxed-out areas, which are prone to error
The particular interest because it is the portion that is most receptors form dimers linked by a disulfide bridge between the significantly implicated in the conformational change to open subunits of neighbouring molecules
Summary
Rapid communication in the nervous system takes place by synaptic transmission, a process in which a neurotransmitter released from a nerve terminal binds transiently to ion channels located in the oppositely facing postsynaptic membrane of the target cell, stimulating the channels to open and effecting a change in membrane potential. Models for the conformational change underlying the postsynaptic response have been derived from both X-ray and cryo-EM studies of several kinds of transmitter-gated ion channel, using recombinant detergent-solubilized protein [for channels in the acetylcholine (ACh) receptor family, see Hibbs & Gouaux, 2011; Miller & Aricescu, 2014; Hassaine et al, 2014; Du et al, 2015; Morales-Perez et al, 2016]. These studies have provided a wealth of structural insight at near-atomic resolution on the channels themselves. Other changes, such as straightening of the adjacent and pore-lining helices, occur, the displacement outwards of near the outer membrane surface is the motion that most directly affects the lipids
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