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

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 Ca2+/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 Ca2+-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.

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

“…These data suggested that activation of VEGF/VEGFR2 signaling is essential for the decreased calcineurin-mediated TRESK reduction and pain hypersensitivity in bone lesion-bearing rats. Our present data, together with previous findings (32)(33)(34)(35)44), suggest that, under cancer conditions, the binding of VEGF to VEGFR2 may activate calcineurin (52,53), trigger NFAT translocated into the nucleus, and enhance the endogenous calcineurin inhibitor RCAN1 (DSCR1). Enhancement of RCAN1 subsequently creates a negative feedback loop to inhibit calcineurin activity, thereby attenuating NFAT nuclear import and the transactivation of its targets such as TRESK (33,36,37) (Fig.…”

Fine‐tuning PERK signaling for neuroprotection

“…Calcineurin inhibitors are already used in the clinic as immunosuppressors, and interestingly there are several reports of neuroprotective effects after calcineurin inhibitor administration (reviewed in (Kipanyula et al . ).…”

Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression

“…In particular, CaN activation was required for the decrease of GABAARs at the synapse in neuronal in vitro model of status epilepticus [3]. Furthermore, CaN inhibitors have anticonvulsant effects in different rodent epilepsy models [2,[4][5][6].…”