{"id":1165,"date":"2026-04-05T16:35:39","date_gmt":"2026-04-05T16:35:39","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=1165"},"modified":"2026-08-26T05:52:14","modified_gmt":"2026-08-26T05:52:14","slug":"ep-receptoren-overview","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=1165","title":{"rendered":"PGE2 functie-spectrum"},"content":{"rendered":"\t\t
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The wideranging functions of prostaglandin E2 and its EP receptors\n<\/h2>\t\t\t\t<\/div>\n\t\t\t\t
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Table 1. Long COVID associated\u00a0SYMPTOMS AND COMORBIDITIES STIMULATED BY PGE2<\/h6>\n<\/td>\n<\/tr>\n
Apnea(1) <\/sup>\u00a0Anemia(2) <\/sup>\u00a0Atherosclerosis(3) <\/sup>\u00a0Asthma(4)<\/sup> Alzheimer(5)<\/sup>\u00a0 Autonomic Dysfunction(6)<\/sup> Bronchoconstriction(7)<\/sup> Cancer(8)<\/sup>\u00a0 Cough(9)<\/sup>\u00a0 Cardiac Hpertrophy(10)<\/sup>\u00a0 Cardiomyopathy(11)<\/sup> Type 1 Diabetes (12)<\/sup>\u00a0 Type 2 Diabetes (13)<\/sup>\u00a0 Dysmenorrhoea(14)<\/sup>\u00a0 Depression(15)<\/sup>\u00a0 Endothelial Dysfunction(16)<\/sup>\u00a0 Gastro-intestinal inflammation (17)<\/sup>\u00a0 IBS(18)<\/sup> Low Blood Pressure(19)<\/sup>\u00a0 Lymphopenia(20)<\/sup>\u00a0 Malaise\/Aversion(21)<\/sup>\u00a0 Migraine(22)<\/sup>\u00a0 Mitochondrial Dysfunction(23-25)<\/sup>\u00a0 Muscle weakness(26)<\/sup> \u00a0 Myalgia(27)<\/sup>\u00a0 Obesity(28)<\/sup>\u00a0 Nausea(29)<\/sup>\u00a0 Neurological conditions(30)<\/sup>\u00a0 Osteoarthritis(31)<\/sup>\u00a0 Pain(32) <\/sup>\u00a0Parkinson(33)<\/sup>\u00a0 (Acute) Kidney Injury(34, 35)<\/sup>\u00a0 Respiratory problems (Asthma)(36) (37) <\/sup>\u00a0Sleep\/Wake problems via EP2\/COX2\/PGD2(38) <\/sup>\u00a0Thirst(39) <\/sup>\u00a0Thrombotic problems via EP3(40)<\/sup> and via EP2>COX2>TXA2(49)<\/sup>\u00a0<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/figure>\n

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Table 2. RECEPTORS EP1 -EP4, AN OVERVIEW (not exhaustive)<\/strong><\/td>\n<\/tr>\n
EP4<\/strong>(41-43)\u00a0\u00a0<\/sup><\/td>\nEP3<\/strong>(41-43)\u00a0\u00a0<\/sup><\/td>\nEP2<\/strong>(41-43)\u00a0\u00a0<\/sup><\/td>\nEP1<\/strong>(41-43)\u00a0\u00a0<\/sup><\/td>\n<\/tr>\n
EP4 has the most affinity for PGE2 of these four receptors (41)<\/sup><\/td>\nEP3 has less affinity for PGE2 than EP4(41)<\/sup><\/td>\nEP2 has less affinity for PGE2 than EP4(41)<\/sup><\/td>\nPGE2 binds the weakest to EP1(41)<\/sup><\/td>\n<\/tr>\n
G-prote\u00efn-coupled(41)<\/sup><\/td>\nG-prote\u00efn-coupled or CA2+ stimulated(41)<\/sup><\/td>\nG-prote\u00efn-coupled(41)<\/sup><\/td>\nCA2+ stimulated(41)<\/sup><\/td>\n<\/tr>\n
cAMP upregulation(41)<\/sup><\/td>\ncAMP downregulation(41)<\/sup><\/td>\ncAMP
upregulation(41)<\/sup><\/td>\n		\u00a0<\/td>\n<\/tr>\n
EP4 desensitizes quickly (when stimulated by a sufficient high level of PGE2 it rapidly internalizes: it moves to the inside of the cell membrane) (41)<\/sup>\u00a0<\/td>\nEight splice variants of this receptor have been identified, some of these upregulate<\/em> cAMP(44, 45)<\/sup><\/td>\nEP2-function is often similar to EP4- function, but PGE2-action through EP2 lasts longer(41)<\/sup><\/td>\nTwo splice variants have been identified. EP1- function is often similar to EP3- function(41)<\/sup><\/td>\n<\/tr>\n
\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n<\/tr>\n
\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n<\/tr>\n
Relaxation of smooth muscle(46)<\/sup>\u00a0<\/td>\nContraction of smooth muscle(46)<\/sup>\u00a0<\/td>\nRelaxation of smooth muscle(46)<\/sup>\u00a0<\/td>\nContraction of smooth muscle(46)<\/sup>\u00a0<\/td>\n<\/tr>\n
Vasodilatation
(46)<\/sup>\u00a0<\/td>\n		Vasoconstriction
(46)<\/sup>\u00a0<\/td>\n		Vasodilatation(46)<\/sup>\u00a0<\/td>\nVasoconstriction(46)<\/sup>\u00a0<\/td>\n<\/tr>\n
Decreasing BP(46)<\/sup>\u00a0<\/td>\nIncreasing BP(46)<\/sup>\u00a0<\/td>\nDecreasing BP(46)<\/sup>\u00a0<\/td>\nIncreasing BP(46)<\/sup>\u00a0\u00a0<\/td>\n<\/tr>\n
Antidiuretic(46)<\/sup>\u00a0<\/td>\nDiuretic(46)<\/sup> Antidiuretic under high salt conditions<\/td>\nAntidiuretic(46)<\/sup><\/td>\nDiuretic(46)<\/sup><\/td>\n<\/tr>\n
PGE2 the major lipid mediator of inflammation stimulates:<\/td>\n<\/tr>\n
through EP4\u00a0<\/td>\nthrough EP3\u00a0<\/td>\nthrough EP2\u00a0<\/td>\nthrough EP1<\/td>\n<\/tr>\n
anti-inflammatory processes, ao downregulating CD4+ activity, stimulating anti-inflammatory cytokines such as il-10 (47)<\/sup>\u00a0<\/td>\ninflammatory processes, ao upregulating inflammatory cytokines such as il-6 (48)<\/sup><\/td>\nby stimulating COX > upregulation of its own production and that of other prostaglandins of the 2-series like PGD2, PGI2 and TXA2(49)<\/sup><\/td>\nan unknown ligand through EP1 can attenuate PGE2 activity through degradation of
COX-2(52, 53)<\/sup><\/td>\n<\/tr>\n
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induces chronic inflammation and various autoimmune diseases through EP4 and EP2 receptors(43, 50)
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induces acute and chronic inflammation, through mast cell activation and T helper differentiation respectively(50)
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(down)regulates expression of COX-2 in the kidney(51)<\/sup><\/td>\n		induces chronic inflammation and various autoimmune diseases through EP4 and EP2 receptors(43, 50)<\/sup><\/td>\n\n

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<\/strong>EP-receptors are expressed on the membranes of all cells, also in the brain, on the membranes of mitochondria(54)<\/sup> and on the nuclear envelope(55)<\/sup><\/td>\n<\/tr>\n
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\u00a0 Expression of EP4\u00a0 In the brain and the CNS and on the membrane of mitochondria, of the nucleus and of cells in the majority of tissues(41)<\/sup><\/p>\n<\/td>\n

\u00a0 Expression of EP3\u00a0 In the brain and the CNS and on the membrane of mitochondria, of the nucleus and of cells in the majority of tissues(41)<\/sup><\/td>\n\u00a0 Expression of EP2\u00a0 In the brain and the CNS. EP2 expression is also detected in lung, kidney, intestinal, glandular tissues, bone marrow, spleen, thymus, tonsils, mucous membranes, and skin(41)<\/sup>\u00a0<\/td>\n\u00a0 Expression of EP1 The EP1 receptor mRNA is ubiquitously expressed and EP1 receptor functions as a constrictor in the smooth muscles of the trachea, gastrointestinal tract, bladder, uterus and is especially expressed in the nervous system(41)<\/sup>\u00a0<\/td>\n<\/tr>\n
\u00a0<\/td>\n<\/tr>\n
PGE2 through EP4<\/td>\nPGE2 through EP3<\/td>\nPGE2 through EP2<\/td>\nPGE2 through EP1<\/td>\n<\/tr>\n
Metabolic<\/em> \u25aa Protects against apoptosis of insulin- producing b\u00e8ta-cells(61)<\/sup> \u25aa Regulates bile acid synthesis, protecting against hyper-
cholesterolemia(62)<\/sup> \u00a0<\/td>\n		Metabolic<\/em> \u25aa Apoptosis of insulin- producing b\u00e8ta-cells(12)<\/sup> \u25aa Negatively regulates glucose-stimulated insulin secretion (GSIS)(56)<\/sup> \u25aa Attenuates lipolysis(57-59)<\/sup> \u25aa Attenuates glycogenolysis (60)<\/sup><\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n<\/tr>\n
Apoptotic<\/em> \u25aa Apoptosis of insulin producing b\u00e8ta-cells(12)<\/sup> \u25aa Apoptosis of neutrophils(63)<\/sup><\/td>\nApoptotic<\/em> \u25aa Protects against apoptosis of insulin producing b\u00e8ta-cells(61)<\/sup><\/td>\nApoptotic<\/em> \u25aa Stimulates apoptosis of oligodendrocyte precursor cells (OPC)(64) <\/sup>that produce myelin \u25aa Apoptosis of neuronal cells in skeletal-muscle(65)<\/sup><\/td>\nApoptotic<\/em> \u25aa Apoptosis of dopaminergic cells in the substantia nigra(66, 67)<\/sup><\/td>\n<\/tr>\n
Brain processes<\/em> \u25aa Inhibition of noradrenergic neurons in the LC(68)<\/sup><\/td>\nBrain processes<\/em> \u25aa Vasodilation involved in migraine(22)<\/sup>\u00a0 \u25aa Anxiolytic-like activity(69)<\/sup><\/td>\nBrain processes<\/em> \u25aa Demyelination of nerves, neurotoxicity \/ cognitive decline by impairing myeloid metabolism(70-73)<\/sup> \u25aa Regulates neurotoxicity induced by aggregated alpha-synuclein(72)<\/sup><\/td>\nBrain processes<\/em> \u25aa GABA -mediated inhibition of dopaminergic neurons in the midbrain(69)<\/sup> \u25aa inflammation-induced aversion(74,75)<\/sup> \u25aa Anxiolytic-like activity(69)<\/sup> \u25aa Suppressing impulse behaviour(76)<\/sup><\/td>\n<\/tr>\n
Nervous system<\/em> \u25aa Inflammatory pain(79)<\/sup> \u00a0<\/td>\nNervous system<\/em> \u25aa Inhibiting endogenous pain control (77)<\/sup> \u25aa Modulating signaling in the autonomic nervous system (PSN and SNS)
(6, 78)<\/sup><\/td>\n		Nervous system<\/em> \u25aa Stimulates apoptosis of oligodendrocyte precursor cells (OPC)(64) <\/sup>that produce myelin \u25aa Apoptosis of neuronal cells in skeletal-muscle(65)<\/sup><\/td>\nBrain processes (follow-up)<\/em> \u25aa EP1 receptor activation increases the probability of status epilepticus and independently promotes hippocampal neurodegeneration(80)<\/sup> \u25aa Behavioral alterations (social avoidance) caused by repeated stress(81, 82)<\/sup> Nervous system \u25aa Pain perception(47)<\/sup><\/td>\n<\/tr>\n
Gastro-intestinal<\/em> \u25aa Inhibition of stomach acid secretion(83)<\/sup>\u00a0 \u25aa Bicarbonate secretion in stomach and duodenum(83)<\/sup>\u00a0<\/td>\nGastro-intestinal<\/em> \u25aa Stimulating mucus secretion(83)<\/sup>\u00a0 \u25aa Bicarbonate secretion in the duodenum(83)<\/sup>\u00a0<\/td>\nGastro-intestinal<\/em><\/td>\nGastro-intestinal<\/em> \u25aa functions as a constrictor in the smooth muscles of the gastrointestinal tract(46)<\/sup> \u25aa Inhibition of gastric motility(83)<\/sup>\u00a0 \u25aa Bicarbonate secretion in the stomach(83)<\/sup>\u00a0 \u25aa Cytoprotection in the stomach(84)<\/sup><\/td>\n<\/tr>\n
Bone, cartilage, muscles \u25aa Cell-proliferation for muscle and bone and other tissue repair \u25aa osteoarthritis(85, 86)<\/sup><\/td>\nBone, cartilage, muscles \u25aa functions as a constrictor(46)<\/sup><\/td>\nBone, cartilage, muscles \u25aa Apoptosis of neuronal cells in skeletal-muscle(65)<\/sup> \u25aa Myalgia(27, 87)<\/sup><\/td>\nBone, cartilage, muscles \u25aa functions as a constrictor in the smooth muscles of the bladder and uterus(46)<\/sup>, possibly involved in the promotion of labor and dysmennorrhea<\/td>\n<\/tr>\n
Cardiovascular<\/em> \u25aa Endothelial barrier integrity
(90-92)<\/sup> \u25aa Inflammatory reaction in atherosclerotic plaques(93)<\/sup> \u00a0<\/td>\n		Cardiovascular<\/em> \u25aa Reduced contractility of the heart(88)<\/sup> \u25aa Cardiac hypertrophy(89)<\/sup> \u25aa Coagulation
thrombosis(40)<\/sup><\/td>\n		Cardiovascular<\/em><\/td>\nCardiovascular<\/em><\/td>\n<\/tr>\n
Lungs<\/em> \u25aa a key role for EP2 and EP4 receptors in microvascular leak (MVL) induced by PGE2(36)<\/sup><\/td>\nLungs<\/em> \u25aa Broncho-constriction, cough(7, 94)<\/sup><\/td>\nLungs
<\/em>
\u25aa Inhibition of bronchoconstriction(95)<\/sup>\u00a0
Suppresses lung innate immunity(96)<\/sup> \u25aa Suppresses allergic sensitization and lung-inflammation(97)<\/sup><\/td>\n		Lungs<\/em> \u25aa functions as a constrictor in the smooth muscles of the trachea(46)<\/sup><\/td>\n<\/tr>\n
Kidneys<\/em><\/td>\nKidneys (EP3)<\/em> EP3 (down)regulates expression of COX-2
in the kidneys(51)<\/sup> Water retention under high salt conditions(98)<\/sup> Edema(43, 99)<\/sup> Role in AKI(34)<\/sup> Attenuates reabsorption\/Role in polyuria(39)<\/sup><\/td>\n		Kidneys (EP1)<\/em> \u25aa Glomerulo-
sclerosis(100)<\/sup> \u25aa Main role in renal fibrosis(101)<\/sup><\/td>\n<\/tr>\n
\u00a0<\/td>\nSkin (EP3)<\/em> \u25aa EP3 and EP1 stimulate melanocyte dendricity \/ skin pigmentation(102)\u00a0\u00a0\u00a0<\/sup><\/td>\n\u00a0<\/td>\n<\/tr>\n
\u00a0<\/td>\nAntagonizing other hormones (EP3)<\/em> \u25aa Inhibition of serotonin signaling; inflammatory pain(103)<\/sup> \u25aa Inhibition of release of noradrenaline and serotonin and dopamine(104-106)<\/sup><\/td>\n\u00a0<\/td>\n<\/tr>\n
All four EP-receptors stimulate cell-proliferation in specific types of cancer(107)<\/sup><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/figure>\n

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