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Na+ ions binding to the bradykinin B2 receptor suppress agonist-independent receptor activation

U Quitterer1, S AbdAlla, K Jarnagin

  • 1Institute of Pharmacology and Toxicology, University of Würzburg, Germany.

Biochemistry
|October 15, 1996
PubMed

Insights

Sodium ions stabilize inactive seven transmembrane domain (7TM) receptors, preventing self-activation. Lowering intracellular sodium triggers constitutive activation of the bradykinin B2 receptor, highlighting sodium

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Seven transmembrane domain (7TM) receptors require balanced activation and inactivation for proper function.
  • Understanding mechanisms that stabilize inactive receptor conformations is crucial to prevent spontaneous signaling.
  • Sodium ions (Na+) are known to influence ligand interactions with various 7TM receptors.

Purpose of the Study:

  • To investigate the role of intracellular sodium concentration in regulating the activation state of the bradykinin B2 receptor (a prototypic 7TM receptor).
  • To elucidate the mechanism by which Na+ ions might stabilize the inactive conformation of 7TM receptors.

Main Methods:

  • Transiently expressed rat B2 receptors in COS-1 cells and used primary human fibroblasts expressing endogenous B2 receptors.
  • Manipulated intracellular Na+ concentrations and measured basal inositol phosphate release as an indicator of receptor activation.
  • Utilized site-directed mutagenesis (Aspartate to Asparagine exchange) to disrupt Na+ interaction with the B2 receptor.
  • Assessed B2 receptor protein phosphorylation levels.

Main Results:

  • Decreasing intracellular Na+ in COS-1 cells expressing B2 receptors led to a 3-fold increase in basal inositol phosphate release, indicating constitutive activation.
  • Reduced intracellular Na+ also increased the intrinsic activity of bradykinin, while elevated Na+ decreased it.
  • Mutating a conserved aspartate residue in transmembrane domain II, preventing Na+ interaction, resulted in constitutive B2 receptor activation.
  • Similar agonist-independent B2 receptor activation was observed in human fibroblasts with decreased intracellular Na+, evidenced by increased basal inositol phosphates and receptor phosphorylation.

Conclusions:

  • Na+ ions interact with the bradykinin B2 receptor to stabilize or induce an inactive receptor conformation.
  • This Na+-dependent mechanism suppresses agonist-independent receptor activation in vivo.
  • The findings reveal a novel regulatory role for intracellular sodium in controlling 7TM receptor signaling.

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