Fig. 2

Postulated multidisciplinary pathway of ME/CFS. ME/CFS onset often occurs following an environmental trigger/s such as infection, trauma or chemical insult. ME/CFS is associated with genetic changes including SNPs in TRP and CHRM that are critical in cell signalling processes. In a two-step process, environmental triggers may result in upregulation of defected proteins that participate in these pathways and disruption of downstream signalling pathways involved in natural killer cell cytotoxicity and mitochondrial regulation. This can either directly affect different tissues and systems or indirectly through inflammatory pathways and cytokines. Cytokines and inflammation trigger epigenetic changes through mRNA or miRNA that further affect physiological function. Ca2⁺, calcium; CN, calcineurin, CaM, Camodulin, CHRM, cholinergic Receptor Muscarinic; cAMP, cyclic adenosine monophosphate, CREB, cyclic adenosine monophosphate response element-binding protein; DAG, diacylglycerol; DHEAs, dehydroepiandrosterone sulfate; DNA, Deoxyribonucleic acid; ERK, extracellular signal-regulated kinase; GDF15, growth/differentiation factor 15; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; IL, interleukin; mTOR, mammalian target of rapamycin; mRNA, messenger ribonucleic acid, MiRNA, micro ribonucleic acid; NFAT, nuclear factor of activated T D cells; PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PACAP, pituitary adenylate cyclase-activating peptide; STIM, stromal interaction molecule; TRP, Transient Receptor Potential; TRPM3, Transient Receptor Potential Melastatin 3; VIP, vasoactive intestinal peptide