From:  Glucocorticoid receptor alpha: origins and functions of the master regulator of homeostatic corrections in health and critical illness

The evolutionary development of homeostatic corrections

NumberStageDescriptionKey pointsApproximate timelineReference
1Ancient origins of steroid signalingEvolution of steroid signaling pathways to regulate metabolism and stress responses in early vertebrates. These pathways allow organisms to manage energy resources and respond to environmental changes.

  • Primitive mechanisms for managing energy resources and responding to environmental changes.

  • Crucial for survival.

Approximately 450–500 million years ago[8]
2Co-evolution with immune, inflammatory, and hemostatic responsesGR co-evolved with the immune system to regulate inflammation and prevent tissue damage. Hemostasis and inflammatory mechanisms evolved alongside, underscoring their interconnected roles.

  • Interaction between GR, NF-κB, AP-1, and hemostasis.

  • Coordinated response to infection, wounds, and tissue protection.

Approximately 400–450 million years ago[11]
3Adaptation to diverse stressorsGR system evolved to manage a wide range of stressors, including infections, injuries, psychological, and metabolic stress.

  • GR as a master regulator.

  • Integrates signals from various pathways to maintain homeostasis.

Approximately 300–350 million years ago[5]
4Integration with mitochondrial functionGR co-evolved with mitochondrial function, reflecting the role of energy production in stress response. Mitochondria contain GREs in mtDNA.

  • Mitochondria originated from symbiosis with proteobacteria.

  • GR-mediated stress response integrated with energy metabolism. mtGREs directly influence mitochondrial gene expression and energy production.

Approximately 1.5–2 billion years ago (mitochondria origin), integration with GR: approximately 400 million years ago[9]
5Essential micronutrients and antioxidant systemsGR-mediated corrections rely on micronutrients and antioxidants incorporated into stress responses as organisms evolved more complex diets and metabolic systems.

  • Micronutrients provided a survival advantage in environments where oxidative stress and energy demands were high.

Approximately 400 million years ago[10]
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This table was generated with the assistance of AI using GPT-4. AP-1: activator protein 1; GR: glucocorticoid receptor; GREs: glucocorticoid response elements; mtDNA: mitochondrial DNA; mtGREs: mitochondrial GREs; NF-κB: nuclear factor-kappa B