From:  Glucocorticoid receptor alpha as a core survival receptor: mechanisms, and implications for health and critical illness

 Distinct and overlapping functions of GRα and MR: systemic roles and consequences of loss.

GRα—key functions and consequences*MR—key functions and consequences
Regulates the function of all organs and circulating immune/non-immune cells; master regulator of homeostasis and homeostatic corrections [10, 83].Sodium and electrolyte homeostasis, including potassium balance and acid-base regulation [87].
Coordinates stress adaptation, metabolism, and mitochondrial function; maintains glucose availability under stress [83, 84].Blood pressure and vascular tone regulation [16, 86].
Controls immune responses, inflammation resolution, and barrier integrity; protects vascular endothelium via eNOS activation and anti-inflammatory signaling [83, 85].Macrophage survival and innate immunity [85].
Supports neurodevelopment and brain resilience [145].Inflammatory regulation and FKBP5 buffering [85].
Integrates systemic communication: vascular, neural, lymphatic; first-line responder to physiological stress [10, 83].Neuroendocrine modulation under stress [146].
Orchestrates transcriptional and non-genomic signaling responses essential for survival during stress [83].Loss leads to salt-wasting, vascular inflammation, and localized immune collapse [86].
Loss causes multisystem failure: including neuronal apoptosis, immune collapse, metabolic breakdown [83, 145].Does not compensate for GRα in systemic regulation; deletion results in regional—not global—physiological failure [86].
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*: GRα is the only receptor proven essential for postnatal survival, serving as a master integrator of systemic homeostasis. It coordinates cross-organ communication, linking metabolic, immune, mitochondrial, neurodevelopmental, and vascular–neural–lymphatic functions through both transcriptional and rapid non-genomic pathways. MR, by contrast, governs more localized processes—such as electrolyte balance, vascular tone, and innate immune activity—that, while vital, cannot substitute for GRα’s system-wide regulatory role. The table compares their distinct and shared functions, outlining the consequences of receptor loss, including multisystem failure with GRα deletion versus compartmentalized dysfunction with MR deletion. GRα: glucocorticoid receptor alpha; MR: mineralocorticoid receptor; eNOS: endothelial nitric oxide synthase; FKBP5: FK506 binding protein 5.