Calcineurin and Its Role in Synaptic Transmission

Abstract

Calcineurin (CaN) is a serine/threonine phosphatase widely expressed in different cell types and structures including neurons and synapses. The most studied role of CaN is its involvement in the functioning of postsynaptic structures of central synapses. The role of CaN in the presynaptic structures of central and peripheral synapses is less understood, although it has generated a considerable interest and is a subject of a growing number of studies. The regulatory role of CaN in synaptic vesicle endocytosis in the synapse terminals is actively studied. In recent years, new targets of CaN have been identified and its role in the regulation of enzymes and neurotransmitter secretion in peripheral neuromuscular junctions has been revealed. CaN is the only phosphatase that requires calcium and calmodulin for activation. In this review, we present details of CaN molecular structure and give a detailed description of possible mechanisms of CaN activation involving calcium, enzymes, and endogenous and exogenous inhibitors. Known and newly discovered CaN targets at pre- and postsynaptic levels are described. CaN activity in synaptic structures is discussed in terms of functional involvement of this phosphatase in synaptic transmission and neurotransmitter release.

Identifying New Substrates and Functions for an Old Enzyme: Calcineurin

“…Use of calcineurin inhibition is associated with a wide range of neurotoxicities, which is consistent with the high concentration of calcineurin in many regions of the brain and its well-documented effects on synaptic transmission and plasticity that underlie demonstrated roles for calcineurin in learning and memory (reviewed in Tarasova et al 2018). These include dephosphorylation of synaptic vesicle proteins to regulate endocytosis and recycling of synaptic vesicles, as well as modulation of N-methyl-Daspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity and cell-surface expression.…”

“…Calcineurin dephosphorylates and activates TRESK, promoting the return of neurons to baseline after signaling, and suggesting a mechanism for calcineurin inhibitors to induce hyperexcitability that would result in pain. Calcineurin also regulates TRPV1, NMDA, and γ-amino butyric acid (GABA) re-ceptors (Tarasova et al 2018), and rats treated with calcineurin inhibitors showed increased pre-and postsynaptic NMDA receptor activity in spinal cords, producing pain hypersensitivity that was reduced with an NMDA receptor inhibitor (Chen et al 2014). Finally, increased vascular tone caused by calcineurin inhibitors might also contribute to CNIPS.…”

Activity-dependent endocytosis of Wingless regulates synaptic plasticity in the Drosophila visual system

“…Since these two genes are involved in neuronal development, the suppression of Wg accumulation observed when these genes are knocked down in RNAi lines is likely due to developmental effects. CanB2 is a regulatory subunit of Calcineurin (CaN), a Ca 2 +calmodulin (Cam: also a hit of the RNAi screen)-activated Ser-Thr protein phosphatase that is essential for the translation of Ca 2 + signals into changes in cell function and development (Tarasova et al, 2018). Recent studies have revealed that the classic substrates of CaN are dephosphins (so named because they are dephosphorylated by CaN) that include dynamins 1 and 3, adaptor protein AP180, lipid phosphatase synaptojanin, and amphiphysin, among others (Sun et al, 2010;Liang et al, 2017).…”

Calcineurin Participation in Hebbian and Homeostatic Plasticity Associated With Extinction

“…Meanwhile, CaN-B has two isoforms: CaN-B1 and CaN-B2, only CaN-B1 binds to CaN-Aα and CaN-Aβ, while CaN-B2 was found only in testes. Each CaN subunit isoform is encoded by an individual gene, which are located in different chromosomes: CaN-Aα in chromosome 4, CaN-Aβ in chromosome 10, and CaN-Aγ in chromosome 8 ( Tarasova et al, 2018 ). In addition to calcineurin, the serine/threonine protein phosphatase family members include protein phosphatases 1 (PP1), 2A (PP2A), and 2C (PP2C) and have different roles on signal transduction in eukaryotic cells ( Rusnak and Mertz, 2000 ).…”