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. 2018 Dec 12;4(1):17–52. doi: 10.3233/BPL-180069

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© 2018 – IOS Press and the authors. All rights reserved

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Fig.4 — Exercise-activated pathways regulating growth, survival, and neuroplasticity. (A) Schematic representation of the effect of increased noradrenaline (NA)–signalling and brain-derived neurotrophic factor (BDNF) / tropomyosin receptor kinase B (TrkB) signalling. Noradrenaline binds to the β-adrenergic receptor (βAR), a G protein–coupled receptor (GPCR) which can initiate a cyclic adenosine monophosophate (cAMP) pathway to phosphorylate (and activate) the transcription factor cAMP response element-binding protein (CREB). In addition, NA–mediated signalling can augment BDNF signalling pathways by transactivating its receptor, TrkB. Phosphorylation of TrkB initiates the phosphatidylinositol-3 kinase (PI-3K) pathway to activate protein kinase B (Akt), which phosphorylates glycogen synthase kinase 3-β (GSK-β), deactivating it, in turn increasing CREB activity. Phosphorylated CREB transcribes a number of pro-survival genes, such as Immediate-Early Gene-Regulatory Element (IEG-RE), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB). In addition, it acts to further promote the transcription of BDNF and TrkB. Proteins that are deactivated by Akt include a number of pro-apoptotic factors (i.e. Casp 9, FKHR, and BAD) (shown in dark grey). Activated proteins and kinases are shown in pinks and blue, and activated CREB, in yellow. Additional abbreviations: adenosine triphosphate (ATP); Bcl-2-associated death promoter (BAD); cAMP response element (CRE); caspase 9 (Casp 9); forkhead transcription factor (FKHR); protein kinase A (PKA); phosphoinositide-dependent protein kinase-1 (PDK-1). (B) Two additional exercise-facilitated pathways involved in the growth, survival and plasticity pathways are the mitogen-activated protein kinases/extracellular signal-regulated kinases pathway (MAPS/ERK) and the phospholipase Cγ/Ca2 + /calmodulin-dependent protein kinase II (PLCγ/CaMKII) pathway. Glutamate NMDA receptors activity also facilitates the effect of exercise on CREB activation. These pathways, like the PI-3K pathway, have also been shown to be involved BDNF/TrkB activation in promoting genes involved in survival and neuroplasticity. Activated proteins and kinases are shown in pinks and blue, and activated CREB, in yellow. Additional abbreviations: Ca^2 + /calmodulin-dependent protein kinase (CAMK), diacyl-glycerol (DAG), Mitogen-activated protein kinase kinase (MEK), inositol trisphosphate (IP3), protein kinase C (PKC) [184, 287, 345, 346].