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Quantifying Agonist Activity at G Protein-coupled Receptors
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Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors

Taka-Aki Koshimizu1, Aki Kashiwazaki1, Junichi Taniguchi1

  • 1Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan.

Scientific Reports
|May 4, 2016
PubMed

Insights

Reducing extracellular sodium enhances agonist binding to G-protein coupled receptors (GPCRs) by minimizing receptor internalization. This study explored combined effects using vasopressin V1b receptors, finding specific ionic conditions optimize cell surface receptor presence.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Biochemistry

Background:

  • Extracellular sodium ions (Na+) can influence G-protein coupled receptor (GPCR) function, potentially affecting agonist binding and receptor trafficking.
  • Previous research has indicated Na+ can mediate a binding block and influence receptor internalization, but combined effects on cell surface receptor availability remain underexplored.

Purpose of the Study:

  • To investigate the impact of reduced extracellular Na+ on both agonist binding and receptor internalization for cell surface GPCRs.
  • To identify specific ionic conditions that can increase the presence of high-affinity receptors at the cell surface while minimizing agonist-induced internalization.

Main Methods:

  • Utilized Chinese Hamster Ovary (CHO) cells expressing vasopressin V1b receptors as a model system.
  • Manipulated extracellular Na+ concentrations and substituted Na+ with other ions (Cs+, NH4+) to assess effects on [(3)H]AVP binding and receptor internalization.
  • Investigated the role of different ionic concentrations and iso-osmotic supplements (glucose, NH4Cl) on V1b receptor trafficking.

Main Results:

  • Decreased extracellular Na+ significantly increased cell surface [(3)H]AVP binding and reduced receptor internalization.
  • Substitution of Na+ with Cs+ or NH4+ inhibited agonist binding, indicating ion-specific effects.
  • Suppression of receptor internalization required NaCl concentrations below 50 mM, highlighting Na+'s critical role in the internalization machinery.
  • Iodide ions were found to inhibit V1b agonist binding.

Conclusions:

  • Specific extracellular ionic conditions can be optimized to enhance the availability of high-affinity vasopressin V1b receptors at the cell surface.
  • Reducing extracellular Na+ concentration is a viable strategy to increase agonist binding while simultaneously decreasing receptor internalization.
  • The findings provide a foundation for understanding and manipulating GPCR cell surface dynamics in response to ionic environmental changes.

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