Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system - 23/07/24
Abstract |
Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Overview of cAMP signaling in oligodendrocytes, microglia, astrocytes, and neurons. Promoting cAMP signaling by either using cAMP stimulators or inhibiting its breakdown enzyme PDE4 boosts different processes in the CNS. cAMP stimulates oligodendrocyte precursor cell differentiation and myelination through PKA and EPAC. PKA mediates these effects via CREB phosphorylation and stimulates ERK1/2, p38 MAPK, and JNK signaling, resulting in phosphorylation and activation of the transcription factor ATF. EPAC can also instigate oligodendrocyte functioning through Raf-mediated activation of ERK1/2, p38 MAPK, and JNK. Elevating cAMP levels in microglia and astrocytes predominately results in PKA-mediated anti-inflammatory effects. PKA can, directly or indirectly via AMPK, inhibit the translocation of NF-κB, leading to reduced production of pro-inflammatory cytokines. Additionally, PKA stimulates the gene expression of anti-inflammatory cytokines through activation of CREB directly or indirectly via JNK, p38 MAPK signaling. Further, EPAC and PKA can decrease neuroinflammation by phosphorylation, and hence inhibition, of GSK3β activity. Besides, EPAC can modulate the inflammatory phenotype of microglia and astrocytes by activating the transcription factor STAT3. Lastly, cAMP is a pivotal modulator in neuronal plasticity, transmission, and survival. Neuronal plasticity is mediated predominantly via PKA and downstream proteins VASP and ERK, leading to CREB activation and gene expression of BDNF, GluA, and Arg1. While PKA stimulates neuronal survival through JNK and CREB phosphorylation and inhibition of NF-κB, EPAC promotes neuronal apoptosis via p38 MAPK and PI3K/AKT/GSK3β/JNK. In addition, the release of multiple neurotransmitters, such as dopamine and glutamate, is promoted by cAMP via PKA/TH and EPAC/PLC signaling. Besides stimulating neurotransmitter release, PKA or indirect PKA/GluA1 promotes receptor trafficking to the plasma membrane. CNS, Central nervous system; AC, Adenylyl cyclase; cAMP, Cyclic adenosine monophosphate; PDE4, Phosphodiesterase 4; PKA, Protein kinase A; EPAC, Exchange proteins activated directly by cyclic AMP; PKC, Protein kinase C; CREB, cAMP-response element binding protein; ATF, Activating transcription factor family; ERK1/2, Extracellular signal-regulated kinase 1/2; MAPK, Mitogen-activated protein kinases; JNK, Jun N-terminal kinase; OPC, Oligodendrocyte precursor cell; AMPK, Adenosine monophosphate-activated protein kinase; GSK3β, Glycogen synthase kinase 3 beta; STAT3, Signal transducer and activator of transcription 3; NF-κB, Nuclear factor κ B; PI3K, Phosphoinositide 3-kinases; Akt, Protein kinase B; VASP, Vasodilator-stimulated phosphoprotein; BDNF, Brain derived neurotrophic factor; GluA, Glutamate transport ATP-binding protein; Arg1, Arginase 1; Bcl-2, B-cell leukemia/lymphoma 2 protein; TH, Tyrosine hydroxylase; PLC, Phospholipase C; DARP, Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa; PP-1, Protein phosphatase 1; DAT, Dopamine transporter; GABAR, Gamma-aminobutyric acid receptor; AMPAR, α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor.
Overview of cAMP signaling in oligodendrocytes, microglia, astrocytes, and neurons. Promoting cAMP signaling by either using cAMP stimulators or inhibiting its breakdown enzyme PDE4 boosts different processes in the CNS. cAMP stimulates oligodendrocyte precursor cell differentiation and myelination through PKA and EPAC. PKA mediates these effects via CREB phosphorylation and stimulates ERK1/2, p38 MAPK, and JNK signaling, resulting in phosphorylation and activation of the transcription factor ATF. EPAC can also instigate oligodendrocyte functioning through Raf-mediated activation of ERK1/2, p38 MAPK, and JNK. Elevating cAMP levels in microglia and astrocytes predominately results in PKA-mediated anti-inflammatory effects. PKA can, directly or indirectly via AMPK, inhibit the translocation of NF-κB, leading to reduced production of pro-inflammatory cytokines. Additionally, PKA stimulates the gene expression of anti-inflammatory cytokines through activation of CREB directly or indirectly via JNK, p38 MAPK signaling. Further, EPAC and PKA can decrease neuroinflammation by phosphorylation, and hence inhibition, of GSK3β activity. Besides, EPAC can modulate the inflammatory phenotype of microglia and astrocytes by activating the transcription factor STAT3. Lastly, cAMP is a pivotal modulator in neuronal plasticity, transmission, and survival. Neuronal plasticity is mediated predominantly via PKA and downstream proteins VASP and ERK, leading to CREB activation and gene expression of BDNF, GluA, and Arg1. While PKA stimulates neuronal survival through JNK and CREB phosphorylation and inhibition of NF-κB, EPAC promotes neuronal apoptosis via p38 MAPK and PI3K/AKT/GSK3β/JNK. In addition, the release of multiple neurotransmitters, such as dopamine and glutamate, is promoted by cAMP via PKA/TH and EPAC/PLC signaling. Besides stimulating neurotransmitter release, PKA or indirect PKA/GluA1 promotes receptor trafficking to the plasma membrane. CNS, Central nervous system; AC, Adenylyl cyclase; cAMP, Cyclic adenosine monophosphate; PDE4, Phosphodiesterase 4; PKA, Protein kinase A; EPAC, Exchange proteins activated directly by cyclic AMP; PKC, Protein kinase C; CREB, cAMP-response element binding protein; ATF, Activating transcription factor family; ERK1/2, Extracellular signal-regulated kinase 1/2; MAPK, Mitogen-activated protein kinases; JNK, Jun N-terminal kinase; OPC, Oligodendrocyte precursor cell; AMPK, Adenosine monophosphate-activated protein kinase; GSK3β, Glycogen synthase kinase 3 beta; STAT3, Signal transducer and activator of transcription 3; NF-κB, Nuclear factor κ B; PI3K, Phosphoinositide 3-kinases; Akt, Protein kinase B; VASP, Vasodilator-stimulated phosphoprotein; BDNF, Brain derived neurotrophic factor; GluA, Glutamate transport ATP-binding protein; Arg1, Arginase 1; Bcl-2, B-cell leukemia/lymphoma 2 protein; TH, Tyrosine hydroxylase; PLC, Phospholipase C; DARP, Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa; PP-1, Protein phosphatase 1; DAT, Dopamine transporter; GABAR, Gamma-aminobutyric acid receptor; AMPAR, α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor.Le texte complet de cet article est disponible en PDF.
Highlights |
• | cAMP is a vital second messenger in a myriad of neurological processes. |
• | Raising cAMP through PDE4 inhibition is a therapeutic strategy for CNS disorders. |
• | Knowledge gap: the effect of PDE4 inhibition on downstream cAMP signaling pathways. |
• | Downstream players of the PDE4/cAMP pathway can be CNS disease targets. |
Keywords : CAMP signaling, Phosphodiesterases, PDE4 inhibition, Central nervous system, Neurodegenerative diseases
Plan
Vol 177
Article 117009- août 2024 Retour au numéro
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