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Cholinergic Neurons: Neurotransmission01:23

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Cholinergic neurotransmission involves the synthesis and the release of acetylcholine (ACh) in order to transmit nerve impulses across the synapse. The process begins with the synthesis of acetyl CoA, a precursor for ACh, from ATP, acetate, and coenzyme A in the mitochondria. Choline, another vital precursor, is transported inside the neuron through choline transporters, including high-affinity choline transporter CHT1, low-affinity choline transporter CTL1, and lower-affinity choline...
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Cholinergic Receptors: Nicotinic01:15

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Nicotinic receptors are ligand-gated ion channels that are activated by acetylcholine and nicotine. Upon activation, they cause a rapid increase in the permeability of cells to K+, Na+, and Ca2+, followed by depolarization and excitation. They are in the autonomic ganglia, skeletal neuromuscular junction, CNS, and adrenal medulla.
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Cholinergic Receptors: Muscarinic01:25

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The pharmacological actions of acetylcholine are elicited via its binding to two families of cholinergic receptors or cholinoceptors, namely, muscarinic and nicotinic receptors. Muscarinic receptors are G protein-coupled receptors and have five subtypes, M1–M5. All mAChR subtypes are activated by acetylcholine and blocked by the antagonist, atropine. 
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Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

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Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
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The ER synthesizes lipids for building cell membranes and performing cellular functions such as energy storage and signaling. The lipid synthesis machinery embedded in the ER membrane primarily collects all reactants from the cytosol. Following synthesis, the secretory pathway and the ER contact sites distribute these lipids to other cellular organelles. Additionally, the energy-rich triacylglycerides are transported from the ER via lipid droplets.
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Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic...
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Structure of a cholinergic cell membrane.

Nigel Unwin1

  • 1Medical Research Council Laboratory of Molecular Biology, CB2 0QH, Cambridge, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|August 15, 2022
PubMed
Summary

Cell membranes feature distinct lipid arrangements. Cholesterol and phospholipids form ordered arrays in the inner leaflet of Torpedo cholinergic membranes, creating a structured layer within the cell membrane.

Keywords:
acetylcholine receptorcholesterolcryo-EMlipid bilayerphospholipid

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Membrane Biophysics

Background:

  • Cell membranes are intricate structures of proteins and lipids with poorly understood molecular interactions.
  • Understanding lipid organization is crucial for elucidating membrane function and dynamics.

Purpose of the Study:

  • To investigate the molecular-level arrangement of phospholipids and cholesterol between nicotinic acetylcholine receptors in the Torpedo cholinergic membrane.
  • To characterize the distinct lipid properties in the inner and outer leaflets of the cell membrane bilayer.

Main Methods:

  • Cryo-electron microscopy was employed to visualize and analyze the lipid-protein interactions.
  • High-resolution imaging allowed for the determination of lipid and cholesterol organization at the molecular level.

Main Results:

  • Lipids displayed different behaviors in the outer and inner membrane leaflets, influenced by protein surfaces and cholesterol concentration.
  • The outer leaflet showed no consistent lipid motif away from proteins, suggesting fluidity.
  • The inner leaflet, with higher cholesterol, exhibited organized, close-packed linear arrays of cholesterol and phospholipid chains, forming a structured layer.

Conclusions:

  • A novel, ordered lipid-cholesterol 'skin' approximately 7 Å thick exists in the inner leaflet of the Torpedo cholinergic membrane.
  • This ordered structure is reminiscent of crystalline monolayers observed at the air-water interface, suggesting conserved lipid packing principles.
  • The findings provide new molecular insights into the complex organization and potential functional implications of lipids within cell membranes.