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Drugs Affecting GI Tract Motility: Dopamine Receptor Antagonists01:28

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Prokinetic agents are specialized medications that stimulate gastrointestinal (GI) motility, promoting food movement through the GI tract. Dopamine, an inhibitory neurotransmitter, plays a significant role in this process, reducing GI motility and indirectly controlling the speed of digestion. Dopamine receptor antagonists, such as metoclopramide and domperidone, offer a unique advantage as prokinetic agents. By blocking the dopamine receptors, these drugs increase GI motility, improving food...
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Brain Slice Biotinylation: An Ex Vivo Approach to Measure Region-specific Plasma Membrane Protein Trafficking in Adult Neurons
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Bile Acids Gate Dopamine Transporter Mediated Currents.

Tiziana Romanazzi1, Daniele Zanella2, Mary Hongying Cheng3

  • 1Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.

Frontiers in Chemistry
|December 27, 2021
PubMed
Summary
This summary is machine-generated.

Bile acids (BAs) regulate brain function by interacting with the dopamine transporter (DAT). Obeticholic acid (OCA) binds DAT non-competitively, suggesting BAs as potential tools for modulating DAT activity and related behaviors.

Keywords:
SLC6bile aciddopamineelectrophysiologymonoaminestransporters

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Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport
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Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Bile acids (BAs) are cholesterol-derived molecules crucial for fat absorption.
  • Emerging evidence highlights BAs' role in regulating brain function.
  • Sterols, including cholesterol, interact with monoamine transporters like the dopamine transporter (DAT).

Purpose of the Study:

  • To investigate the interaction between the bile acid obeticholic acid (OCA) and the dopamine transporter (DAT).
  • To characterize how OCA regulates DAT activity using electrophysiology and molecular modeling.

Main Methods:

  • Expressed murine DAT (mDAT) in Xenopus laevis oocytes.
  • Utilized electrophysiology to measure DAT-mediated currents.
  • Performed molecular docking simulations to elucidate binding mechanisms.

Main Results:

  • OCA induced a transient, Na+-dependent inward current via DAT, independent of intracellular calcium.
  • OCA transiently blocked the DAT-mediated Li+-leak current, indicating direct binding.
  • OCA interacted with DAT non-competitively with respect to dopamine (DA).
  • Molecular modeling identified two potential OCA binding sites on DAT, one involving D421 and another involving R445 and D436.

Conclusions:

  • Bile acids, such as OCA, can directly interact with and modulate DAT function.
  • OCA's interaction may stabilize an inward-facing open state of DAT, affecting DA transport.
  • Bile acids represent potential novel pharmacological agents for regulating DAT activity and associated behaviors.