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Related Concept Videos

Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

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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.
The direct-acting...
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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: 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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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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Direct-Acting Cholinergic Agonists: Pharmacokinetics01:31

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Direct-acting cholinergic agonists, such as synthetic choline esters and naturally occurring alkaloids, exert their effects by enhancing the actions of acetylcholine and stimulating the parasympathetic nervous system. Synthetic choline esters share structural similarities with acetylcholine. For example, they have a positively charged quaternary ammonium or onium group, contributing to their hydrophilic characteristics. As a result, they are poorly absorbed in the body through oral...
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Cholinergic Antagonists: Chemistry and Structure-Activity Relationship01:29

Cholinergic Antagonists: Chemistry and Structure-Activity Relationship

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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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Related Experiment Video

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Probing Nicotinic Acetylcholine Receptor Function in Mouse Brain Slices via Laser Flash Photolysis of Photoactivatable Nicotine
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Molecular recognition at cholinergic synapses: acetylcholine versus choline.

Iva Bruhova1, Anthony Auerbach1

  • 1Department of Physiology and Biophysics, SUNY at Buffalo, Buffalo, NY, 14214, USA.

The Journal of Physiology
|October 26, 2016
PubMed
Summary

Neuromuscular acetylcholine receptors distinguish acetylcholine from choline based on binding energy differences. Hydrogen bonds position acetylcholine optimally, while choline is misaligned, leading to weaker interactions and lower affinity.

Keywords:
agonistcation-piion channelneuromuscularreceptor

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • Neuromuscular acetylcholine receptors (AChRs) bind acetylcholine (ACh) with high affinity and its metabolite choline (Cho) with low affinity.
  • AChRs are exposed to high concentrations of both ACh and Cho at the nerve-muscle synapse.
  • Understanding the molecular basis of AChR ligand discrimination is crucial for synaptic function.

Purpose of the Study:

  • To investigate how neuromuscular acetylcholine receptors differentiate between acetylcholine (ACh) and choline (Cho).
  • To determine the role of specific amino acid residues and their interactions in ligand binding affinity.

Main Methods:

  • Single-channel electrophysiology was used to measure resting affinities of adult-type mouse AChRs.
  • Mutations were introduced at transmitter-binding sites to assess their impact on ligand binding.
  • Binding free energies for ACh and Cho were compared.

Main Results:

  • Aromatic residues (αY190, αW149, αY198) contribute approximately 50% less binding energy for Cho compared to ACh.
  • Deprotonation of αY190 by αK145 strengthens interactions with the quaternary ammonium group of both ligands.
  • Hydrogen bonds dictate distinct ligand positions, optimizing ACh binding while misaligning Cho, resulting in differential affinities.

Conclusions:

  • Ligand discrimination by AChRs is achieved through differential positioning within a fixed protein structure.
  • Specific interactions, including deprotonation of αY190 and hydrogen bonding, are critical for high-affinity ACh binding and low-affinity Cho binding.
  • These findings elucidate the molecular mechanisms underlying neurotransmitter and metabolite recognition at the neuromuscular junction.