COVID-19, Long COVID, PGE2, imbalanced EP3 capacity and hormonal resistance, are they interrelated?

Research suggests that COVID-19, LC, and resistance phenomena such as type 2 diabetes (T2D) and obesity are interrelated ¹. Both PGE2 and lack or excess of EP3 receptor expression have been reported to play crucial, yet incompletely understood, roles in insulin resistance or (T2D) and leptin resistance or obesity ^2-7. We propose that the initial upregulation of PGE2 induced by SARS-CoV-2 infection may, in some individuals, persist beyond the acute phase, associated with altered EP3 receptor function. This imbalance may pre-exist and/or be further amplified by sustained PGE2 elevation during infection. Such alterations in EP3 signaling could contribute to homeostatic dysregulation and presumed resistance phenomena, as discussed in the following sections.

How could PGE2 antagonize other mediators, promoting resistance?

We previously noted that several PGE2 stimulating agents and are also antagonized by PGE2, including acetylcholine (ACh) ⁸, angiotensin II (Ang II) ⁹, AVP ¹⁰, serotonin (5-HT) ¹¹, dopamine (DA) ¹², fibroblast growth factor 23 (FGF23) ¹³, and interferon-gamma (IFN-γ) ¹⁴. We identified several pathways by which PGE2 could antagonize the activity of other agents:

1. Stimulating functional autoantibodies (aabs) to the receptors of other agents and their class switching (through EP2/EP4)
2. Stimulating phosphorylation of their receptors, possibly attracting autoantibodies (through EP1)
3. Downregulation of their secretion (through EP3)
4. Indirect functional antagonism of GPCRs through shared subcellular pathways

Stimulating autoantibodies and their class switching

Upregulation of autoantibodies (aabs) of the immunoglobulin G (IgG) class to GPCRs has been observed in both COVID-19 ^15,16and LC patients ^17,18. Animals experimentally infected with SARS-CoV-2 also generate functional aabs against GPCRs ¹⁹.

PGE2 has been shown to stimulate the production and class switching of autoantibodies from the immunoglobulin M (IgM) to IgG ²⁰ or IgE types ^{21 22,23}, through the cAMP pathway (EP2/EP4) ²⁴. Aabs can modulate the binding of true ligands. We suggest that PGE2 may hinder ligand binding in COVID-19 and LC through aab production ^25,26. 

Stimulating phosphorylation processes

Another pathway involves stimulation of phosphorylation processes by PGE2 ^27-29. We suggest that PGE2 could interfere with receptor binding of specific compounds by promoting receptor or ligand phosphorylation, including via the EP1 PKC pathway ³⁰. Phosphorylation has been reported to increase the binding of aabs by up to 2- or 7-fold ^31,32.

Downregulation of the secretion of other agents

PGE2 reportedly inhibits the secretion of other hormones through receptor EP3, such as: ACh ³³, insulin ³⁴and dopamine ³⁵, noradrenaline ³⁶ and serotonin ³⁶.

Indirect functional antagonism of GPCR-ligands through shared subcellular pathways

EP receptors belong to the class of the G-protein coupled receptors (GPCRs). Reportedly, PGE2 dominance could interfere with the signaling of other GPCR-binding hormones that use the same downstream signaling pathways ³⁷. GPCR signaling depends on a finite pool of Gi or Gs proteins and other downstream second messengers. The EP3 receptor is Gi-coupled, and EP2 and EP4 are Gscoupled ³⁸. Many other monoamine receptors are Gi-, Gs-, or Gq-coupled as well.

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