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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
07:41

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

Published on: February 20, 2018

Nongenomic testosterone calcium signaling. Genotropic actions in androgen receptor-free macrophages

Zhiyong Guo1, W Peter M Benten, Jürgen Krücken

  • 1Division of Molecular Parasitology and the Centre of Biological Medical Research, Heinrich-Heine University, 40225, Düsseldorf, Germany.

The Journal of Biological Chemistry
|June 6, 2002
PubMed

Insights

Testosterone can act independently of intracellular androgen receptors via membrane receptors, rapidly increasing intracellular calcium. This nongenomic signaling modulates lipopolysaccharide responses through p38 MAPK pathways.

Area of Science:

  • Endocrinology
  • Cell Signaling
  • Immunology

Background:

  • Steroid hormones, including testosterone, typically exert effects via intracellular nuclear receptors.
  • Non-genomic signaling pathways offer alternative mechanisms for rapid cellular responses.
  • The role of plasma membrane androgen receptors (mAR) in testosterone's rapid actions is an area of ongoing investigation.

Purpose of the Study:

  • To investigate testosterone's genotropic actions independent of intracellular androgen receptors (iAR).
  • To elucidate the role of plasma membrane androgen receptors (mAR) in testosterone-induced rapid cellular signaling.
  • To explore the cross-talk between testosterone's nongenomic signaling and lipopolysaccharide (LPS) pathways.

Main Methods:

  • Utilized iAR-free murine RAW 264.7 macrophages.
  • Measured intracellular free Ca(2+) concentration changes.
  • Assessed activation of MAPK pathways (ERK1/2, p38, JNK/SAPK), c-fos promoter activity, and NO production.
  • Employed BAPTA (Ca(2+) chelator) and SB 203580 (p38 inhibitor) to probe signaling mechanisms.

Main Results:

  • Testosterone rapidly increased intracellular Ca(2+) via mAR in iAR-free cells, independent of iAR and estrogen receptors.
  • This nongenomic testosterone signaling did not directly activate MAPK, c-fos, or NO production.
  • Testosterone attenuated LPS-induced c-fos promoter activation and NO production, dependent on Ca(2+) and involving p38 MAPK.
  • Testosterone's attenuation of LPS-induced p38 activation was also Ca(2+)-dependent.

Conclusions:

  • Testosterone exerts nongenomic actions via mAR, leading to rapid Ca(2+) signaling.
  • This mAR-mediated signaling pathway interacts with LPS signaling through p38 MAPK.
  • Testosterone's nongenomic Ca(2+) signaling influences cell function by modulating inflammatory responses.
  • This study reveals a novel cross-talk mechanism between mAR-mediated testosterone signaling and innate immune pathways.

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