Calcineurin in memory and bidirectional plasticity

doi:10.1016/j.bbrc.2003.10.046

Biochemical and Biophysical Research Communications

Volume 311, Issue 4, 28 November 2003, Pages 1195-1208

https://doi.org/10.1016/j.bbrc.2003.10.046 Get rights and content

Abstract

The molecular mechanisms of learning and memory, and the underlying bidirectional changes in synaptic plasticity that sustain them largely implicate protein kinases and phosphatases. Specifically, Ca²⁺-dependent kinases and phosphatases actively control neuronal processing by forming a tightly regulated balance in which they oppose each other. In this balance, calcineurin (PP2B) is a critical protein phosphatase whose main function is to negatively modulate learning, memory, and plasticity. It acts by dephosphorylating numerous substrates in different neuronal compartments. This review outlines some of CN neuronal targets and their implication in synaptic functions, and describes the role of CN in the acquisition, storage, retrieval, and extinction of memory, as well as in bidirectional plasticity.

Section snippets

CN is present in multiple neuronal compartments

Neuronal cells are very rich in CN and multiple neuronal processes depend on CN activity. CN appears to have distinct functions in various neuronal compartments, in part due to the different nature and abundance of its substrates and regulatory proteins in these compartments. To illustrate the variety and specificity of CN actions in neurons, the following section will describe some of the CN-dependent mechanisms in pre- and postsynaptic terminals, the cytoplasm or the nucleus.

Several phases of learning and memory are regulated by CN

The Ca²⁺ sensitivity, abundance, multiplicity of substrates, sites of action, and regulation mechanisms of CN in neuronal cells make it a potentially critical player in brain functions. Until recently, its role in learning and memory was not well understood. In the last couple of years, pharmacological and genetic studies have provided new insight into its involvement in signaling pathways that regulate learning and memory.

CN in synaptic transmission and plasticity

Although the requirement for CN in learning and memory is firmly demonstrated, the refined cellular and molecular mechanisms that are recruited by CN are not fully understood. It is recognized that CN can modulate synaptic transmission and plasticity, and thereby influence the efficacy of information processing in brain cells. The section below summarizes the current understanding of this aspect of CN functions.

Conclusion

In addition to the obvious relevance of CN-mediated signaling in learning, memory, and plasticity, many of the molecular pathways and cellular processes regulated by CN in the brain have broad physiological and clinical impact. Thus, CN is associated with many brain disorders including stroke, epilepsy, chronic stress, Alzheimer’s and Huntington’s diseases, amyotrophic lateral sclerosis, dementia, fear disorders, Down syndrome, or schizophrenia. It is therefore of prime importance to better

Acknowledgements

Research in I.M.M. lab is supported by the Swiss Federal Institute of Technology, Swiss National Science Foundation, NCCR Neural Plasticity and Repair, EMBO Young Investigator Program, Roche Research Foundation, Borderline Personality Research Foundation, Human Frontier Science Program, and UBS Bank. Many thanks to Harma Feitsma for help with the bibliography.

References (146)

J.L Yakel
Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription
Trends Pharmacol. Sci.
(1997)
M Hosaka et al.
A phospho-switch controls the dynamic association of synapsins with synaptic vesicles
Neuron
(1999)
P Chi et al.
Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies
Neuron
(2003)
J.C Lievens et al.
Abnormal phosphorylation of synapsin I predicts a neuronal transmission impairment in the R6/2 Huntington’s disease transgenic mice
Mol. Cell. Neurosci.
(2002)
B Marks et al.
Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals
Curr. Biol.
(1998)
M.A Cousin et al.
The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis
Trends Neurosci.
(2001)
H Kuromi et al.
An inhibitory role of calcineurin in endocytosis of synaptic vesicles at nerve terminals of Drosophila larvae
Neurosci. Res.
(1997)
M.M Lai et al.
The calcineurin–dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis
J. Biol. Chem.
(1999)
R Bauerfeind et al.
Amphiphysin I is associated with coated endocytic intermediates and undergoes stimulation-dependent dephosphorylation in nerve terminals
J. Biol. Chem.
(1997)
M.M Lai et al.
Cain, a novel physiologic protein inhibitor of calcineurin
J. Biol. Chem.
(1998)

M.M Lai et al.

The calcineurin-binding protein cain is a negative regulator of synaptic vesicle endocytosis

J. Biol. Chem.

(2000)

E.M Quinlan et al.

Postsynaptic mechanisms for bidirectional control of MAP2 phosphorylation by glutamate receptors

Neuron

(1996)

M Colledge et al.

Targeting of PKA to glutamate receptors through a MAGUK–AKAP complex

Neuron

(2000)

D.L Armstrong

Calcium channels regulation by calcineurin, a Ca²⁺-activated phosphatase in mammalian brain

Trends Neurosci.

(1989)

T.C Chen et al.

Identification of soluble protein phosphatases that dephosphorylate voltage-sensitive sodium channels in rat brain

J. Biol. Chem.

(1995)

T Kondratyuk et al.

Depolarization of rat brain synaptosomes increases phosphorylation of voltage-sensitive sodium channels

J. Biol. Chem.

(1997)

I.M Raman et al.

Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase

Neuron

(1996)

J.J Krupp et al.

Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors

Neuropharmacology

(2002)

J Shi et al.

Activity-dependent induction of tonic calcineurin activity mediates a rapid developmental downregulation of NMDA receptor currents

Neuron

(2000)

C.M Norris et al.

Calcineurin enhances L-type Ca(2+) channel activity in hippocampal neurons: increased effect with age in culture

Neuroscience

(2002)

A.M Cameron et al.

Calcineurin associated with the inositol 1,4,5-trisphosphate receptor–FKBP12 complex modulates Ca²⁺ flux

Cell

(1995)

A.M Cameron et al.

FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine–proline (1400–1401) and anchors calcineurin to this FK506 domain

J. Biol. Chem.

(1997)

D Guerini et al.

Calcineurin controls the expression of isoform 4CII of the plasma membrane Ca²⁺ pump in neurons

J. Biol. Chem.

(2000)

L Li et al.

Calcineurin controls the transcription of Na+/Ca²⁺ exchanger isoforms in developing cerebellar neurons

J. Biol. Chem.

(2000)

G.R Crabtree

Calcium, calcineurin, and the control of transcription

J. Biol. Chem.

(2001)

H Bito et al.

CREB phosphorylation and dephosphorylation: a Ca²⁺- and stimulus duration-dependent switch for hippocampal gene expression

Cell

(1996)

B.E Lonze et al.

Function and regulation of CREB family transcription factors in the nervous system

Neuron

(2002)

K.T Chang et al.

Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons

Neuron

(2001)

I.A Graef et al.

Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons

Cell

(2003)

J Lisman

The CaM kinase II hypothesis for the storage of synaptic memory

Trends Neurosci.

(1994)

J.E Lisman et al.

A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly

Neuron

(2001)

K Fukunaga et al.

A working model of CaM kinase II activity in hippocampal long-term potentiation and memory

Neurosci. Res.

(2000)

P.C Bennett et al.

Cyclosporin A, FK506 and rapamycin produce multiple, temporally distinct, effects on memory following single-trial, passive avoidance training in the chick

Brain Res.

(2002)

P.C Bennett et al.

Peptidyl-prolyl-cis/trans-isomerase activity may be necessary for memory formation

FEBS Lett.

(1998)

S Ikegami et al.

Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction

Neuroscience

(2000)

S.H Snyder et al.

Immunophilins in the nervous system

Neuron

(1998)

I.M Mansuy et al.

Restricted and regulated overexpression reveals calcineurin as a key component of the transition from short-term to long-term memory

Cell

(1998)

I.M Mansuy et al.

Inducible and reversible gene expression with the rtTA system for the study of memory

Neuron

(1998)

G Malleret et al.

Reversible enhancement of learning, memory and long-term potentiation by genetic inhibition of the protein phosphatase calcineurin

Cell

(2001)

H Zeng et al.

Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory

Cell

(2001)

J.A Cummings et al.

Ca²⁺ signaling requirements for long-term depression in the hippocampus

Neuron

(1996)

M.F Bear

Mechanism for a sliding synaptic modification threshold

Neuron

(1995)

A.J Heynen et al.

Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo

Neuron

(2000)

P.T Huerta et al.

Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro

Neuron

(1995)

D.J.A Wyllie et al.

A role for protein kinases and phosphatases in the Ca²⁺-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses

Neuron

(1994)

T.S Sihra et al.

Localized Ca²⁺ entry preferentially effects protein dephosphorylation, phosphorylation, and glutamate release

J. Biol. Chem.

(1992)

T.S Sihra et al.

A role for calcineurin (protein phosphatase-2B) in the regulation of glutamate release

Biochem. Biophys. Res. Commun.

(1995)

C.B Klee et al.

Calcineurin: a calcium- and calmodulin-binding protein of the nervous system

Proc. Natl. Acad. Sci. USA

(1979)

C.B Klee et al.

The calmodulin-regulated protein phosphatase

D.G Winder et al.

Roles of serine/threonine phosphatases in hippocampal synaptic plasticity

Nat. Rev. Neurosci.

(2001)

Cited by (166)

Dibutyl phthalate disrupts glycogen synthase kinase 3α essential for sperm motility
2024, Ecotoxicology and Environmental Safety
To unravel the toxic mechanism of phthalate ester plasticizer endocrine disruptor in spermatozoa, we examined the effect of dibutyl phthalate (DBP) on the stability and inhibitory phosphorylation of glycogen synthase kinase 3α (GSK3α), a protein kinase crucial for sperm motility in mice. In DBP-treated spermatozoa, reactive oxygen species (ROS) and lipid peroxide were significantly increased. In computer-assisted sperm analysis, DBP at concentrations of 10 – 100 μg/mL significantly decreased total motility and progressive motility of spermatozoa. On western blots, DBP decreased p-GSK3α(Ser21) and increased p-GSK3α(Tyr279) in spermatozoa. Similarly, hydrogen peroxide decreased p-GSK3α(Ser21) but not p-GSK3α(Tyr279) in spermatozoa. Immunofluorescent labeling demonstrated that DBP markedly decreased immunoreactivities of GSK3α and p-GSK3α(Ser21) but increased immunoreactivity of p-GSK3α(Tyr279) in spermatozoa. DBP at a concentration of 100 μg/mL significantly increased phosphatase activity in spermatozoa. Calyculin A, a protein phosphatase 1 and 2 A inhibitor, markedly increased p-GSK3α(Ser21) and sperm motility and attenuated a DBP-induced decrease of p-GSK3α(Ser21) and sperm motility. On western blot, 1–100 μg/mL DBP decreased GSK3α in spermatozoa. On immunoprecipitation western blot, DBP at 10 - 100 μg/mL increased polyubiquitinated sperm proteins including GSK3α. The MG115, proteasome inhibitor attenuated degradation of GSK3α in DBP-treated spermatozoa. Hydrogen peroxide at 10 μM increased polyubiquitinated sperm proteins, suggesting that DBP may increase ubiquitination of GSK3α via ROS induction. Together, DBP may decrease the cellular amount of GSK3α through the ubiquitin-proteasome pathway and p-GSK3α(Ser21) through ROS generation and activation of protein phosphatases, impairing sperm motility.
Pin1 and Alzheimer's disease
2023, Translational Research
Citation Excerpt :
Aβ42 signaling is known to upregulate CaN activity in cells104,105 and CaN expression in patients and AD animal models is elevated.105,106 Conversely, CaN normalization restores synaptic plasticity,107 dendritic spine density108 and learning and memory.109,110 However, complete knock-down of CaN inhibited working memory111 and synaptic plasticity112 demonstrating that normal brain function requires CaN expression and activity within a tightly controlled range.
Alzheimer's disease (AD) is an immense and growing public health crisis. Despite over 100 years of investigation, the etiology remains elusive and therapy ineffective. Despite current gaps in knowledge, recent studies have identified dysfunction or loss-of-function of Pin1, a unique cis-trans peptidyl prolyl isomerase, as an important step in AD pathogenesis. Here I review the functionality of Pin1 and its role in neurodegeneration.
Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin
2022, Biochemistry and Biophysics Reports
Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC₅₀. Interestingly, the inhibitors identified from the screen do not inhibit phosphoprotein phosphatase 2A, a member of the serine/threonine phosphatase family that shares 43% sequence identity with the CaN active site. The pharmacophore model that we developed and validated in this work may help to accelerate the development of specific CaN inhibitors.
A cross-talk between nitric oxide and the glutamatergic system in a Shank3 mouse model of autism
2022, Free Radical Biology and Medicine
Nitric oxide (NO) is a multifunctional signaling molecule that plays a crucial role in synaptic transmission and neuronal function. Pioneering studies show that nitric oxide (NO) and S-nitrosylation (SNO, the NO-mediated posttranslational modification) can engender nitrosative stress in the brain, contributing to neurodegenerative diseases. Little is known, however, about the aberrant NO signaling in neurodevelopmental disorders including autism spectrum disorder (ASD). We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive NO levels and aberrant protein SNO. The glutamatergic system is involved in ASD, specifically in SHANK3 pathology. We used SNOTRAP technology to identify the SNO-proteome in the brain of the Shank3 mutant mice to understand the role of SNO in the glutamatergic system during the development of these mice. We conducted a systems biology analysis of the SNO-proteome to investigate the biological processes and signaling pathways in the brain of juvenile and adult Shank3 mutant and wild-type mice. The Shank3 mutation caused significant SNO-enrichment of a glutamate signaling pathway in the juvenile and adult mutant mice, although different protein subsets were S-nitrosylated in both ages. Cellular compartments analysis showed that “glutamatergic Synapse“ is SNO-enriched significantly in the mutant mice of both ages. We also found eight S-nitrosylated proteins involved in glutamate transmission in both ages. 38 SNO-proteins found in the mutant mice are among the high-risk SFARI gene list. Biochemical examination shows a reduction in the levels of NMDA Receptor (NR1) in the cortex and striatum of the mutant mice of both ages. Neuronal NOS knockdown in SHSY-5Y rescued NR1 levels. In conclusion, this study reveals novel SNO of key glutamatergic proteins in Shank3 mutant mice and a cross-talk between nitric oxide and the glutamatergic system.
Neurologic Toxicities Associated with Tumor Necrosis Factor Inhibitors and Calcineurin Inhibitors
2020, Neurologic Clinics
Melatonin inhibits Japanese encephalitis virus replication and neurotoxicity via calcineurin-autophagy pathways
2023, BMC Neuroscience

View all citing articles on Scopus

View full text

Calcineurin in memory and bidirectional plasticity

Abstract

Section snippets

CN is present in multiple neuronal compartments

Several phases of learning and memory are regulated by CN

CN in synaptic transmission and plasticity

Conclusion

Acknowledgements

Trends Pharmacol. Sci.

Neuron

Neuron

Mol. Cell. Neurosci.

Curr. Biol.

Trends Neurosci.

Neurosci. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuron

Trends Neurosci.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuropharmacology

Neuron

Neuroscience

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Neuron

Neuron

Cell

Trends Neurosci.

Neuron

Neurosci. Res.

Brain Res.

FEBS Lett.

Neuroscience

Neuron

Cell

Neuron

Cell

Cell

Neuron

Neuron

Neuron

Neuron

Neuron

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Calcineurin: a calcium- and calmodulin-binding protein of the nervous system

Proc. Natl. Acad. Sci. USA

The calmodulin-regulated protein phosphatase

Roles of serine/threonine phosphatases in hippocampal synaptic plasticity

Nat. Rev. Neurosci.