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Review
. 2016:2016:5081021.
doi: 10.1155/2016/5081021. Epub 2016 Aug 15.

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Maulilio John Kipanyula  1 , Wahabu Hamisi Kimaro  1 , Paul F Seke Etet  2
Affiliations
Review

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Maulilio John Kipanyula et al. J Aging Res. 2016.

Abstract

The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca(2+)/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca(2+)-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

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Figures

Figure 1
Figure 1
Calcineurin/NFAT signaling pathway. Calcineurin/nuclear factor of activated T-lymphocytes (NFAT) signaling activation in the nervous system is mainly induced by neurotrophins via their tyrosine kinase receptors, glutamate receptors, and nonligand-dependent receptors, such as voltage-gated Ca2+ channels in hippocampal neurons. The genes transcribed and the effects of these signaling pathways are cell-type dependent. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; GSK3, glycogen synthase kinase 3; IGF1R, insulin-like growth factor 1 receptor; IP3R, inositol 1,4,5-trisphosphate receptor; NF-κB, nuclear factor kappa B; NFATc, Ca2+-regulated NFATs; NGF, neurotrophin nerve growth factor; NMDA, N-methyl-D-aspartic acid; RCAN1, regulator of calcineurin 1; RyR; ryanodine receptor; TrkA, tropomyosin receptor kinase type 1; TrkB, tropomyosin receptor kinase type 2.
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