Structure of a cholinergic postsynaptic membrane

Unwin PNT

MRC Laboratory of Molecular Biology, Cambridge UK.

Cholinergic postsynaptic membranes are specialized membranes of the nerve-muscle synapse, designed to depolarise rapidly when activated by the transmitter acetylcholine (ACh) released from a nerve terminal into the synaptic cleft. The resident postsynaptic ion channels, nicotinic ACh receptors, mediate the electrical response by opening cation-selective pathways across the muscle cell membrane, signaling the muscle to contract. Membrane lipids are known to play a vital role in this process, which we are currently investigating by cryo-EM, using postsynaptic membranes from the Torpedo electric ray. We find that cholesterol segregates away from the phospholipids in the vicinity of the ACh receptors, associating robustly with specific transmembrane sites and forming microdomain bridges between neighbouring protein molecules. The cholesterol-interacting parts of the receptor are those most directly implicated in controlling cation conductance and gating of the channel. Since cholesterol harbors a sterol group it would confer local rigidity to the membrane, particularly when packed side-by-side as in a microdomain. Our results suggest that such structural support is needed to stabilize the transmembrane architecture and to restrict mobility to relevant regions of the protein so that a productive conformational change occurs upon acetylcholine release, ensuring a maximal depolarizing response.