This association changes physiochemical properties of the membrane; activating membrane proteins, altering cellular functions and ultimately influencing cation transport through the plasma membrane and stimulating the proton leak across the inner mitochondrial membrane. Hindered oxidative phosphorylation compromises ATP production, a major energy source for cellular energy metabolism and immune function. In vivo studies of Con-A stimulated thymocytes (in rats) and human immune cells that were administered high doses of methylprednisolone has been shown to inhibit respiration in a dose-dependent manner, inhibit plasma calcium and sodium uptake, and increase cytoplasmic calcium concentration. The summative process is as follows: Methylprednisolone intercalates in the plasma membrane, causes physiochemical changes, activates membrane proteins that inhibit plasma calcium and sodium uptake (mimicking an energy deficit state). ATP consumption drops (resembled by inhibited respiration), resulting in protein permeability at the inner mitochondrial membrane and uncoupling of oxidative phosphorylation. Of notable importance, DNA/RNA synthesis was not hindered. The dependency of house keeping cells and immune cells on ATP, results in immunosuppression during ATP deficit. Specific immune functions effected by this process are cytokinesis, migration, phagocytosis, antigen processing and presenting, antibody synthesis, cytotoxicity and regulation. The HPA axis
The activation of the hypothalamic-pituitary axis (HPA axis) stimulates the production of endogenous glucocorticoids within the adrenal cortex. The HPA axis interprets stimuli (stress, inflammation and circadian cues) and transduces a corresponding physiochemical response. Glucocorticoids released in the blood, serve as a messenger by binding to glucocorticoid receptors in a wide distribution across the body, including the HPA axis itself.
Genomic signaling
Genomic mechanisms, regardless of which type, elicit responses with a slow onset and a slow dissipation. This is attributed to the duration of mRNA transcription and translation. Glucocorticoids have the ability to regulate roughly 100 to 1000 genes with specificity to cell-type.Three major mechanisms have described how the MP-GR complex alter gene expression by either binding to DNA or transcription modulators. One mechanism of genomic signaling occurs when the MP-GR complex directly binds to DNA sequences called glucocorticoid response elements (GREs). GREs are located in regulatory regions of target genes and mediate their transactivation or transrepression. For example, the activation of lipocortin 1 (ANAX1) negatively interferes with the production of prostaglandins and leukotrienes, known pro-inflammatory signals. Likewise, negative GREs (nGREs) are responsible for repressing genes involved in immune cell activation. Post transcriptional  modifications
Post translational modifications (PTMs) also contribute to methylprednisolone signaling and can produce genomic and non-genomic effects. The GR has contains several sites for phosphorylation, sumoylation, ubiquitination, and acetylation that primarily occurs after intracellular methylprednisolone binding to the GR. PTMs modulate many functions including nuclear translocation, strength and duration of receptor signaling and cofactor interaction. A specific example is the deacetylation by histone deacetylase 2 (HDACe) was necessary for transrepression of  NF-κB. Non-genomic signaling
The mechanisms of non-genomic signaling are distinct from genomic signaling, yet mediate similar pathways and provide therapeutic relevance.