Trends in Neurosciences
Volume 23, Issue 2, 1 February 2000, Pages 75-80
Journal home page for Trends in Neurosciences

Review
Postsynaptic protein phosphorylation and LTP

https://doi.org/10.1016/S0166-2236(99)01490-3Get rights and content

Abstract

Prolonged changes in synaptic strength, such as those that occur in LTP and LTD, are thought to contribute to learning and memory processes. These complex phenomena occur in diverse brain structures and use multiple, temporally staged and spatially resolved mechanisms, such as changes in neurotransmitter release, modulation of transmitter receptors, alterations in synaptic structure, and regulation of gene expression and protein synthesis. In the CA1 region of the hippocampus, the combined activation of SRC family tyrosine kinases, protein kinase A, protein kinase C and, in particular, Ca2+/calmodulin-dependent protein kinase II results in phosphorylation of glutamate-receptor-gated ion channels and the enhancement of subsequent postsynaptic current. Crosstalk between these complex biochemical pathways can account for most characteristics of early-phase LTP in this region.

Section snippets

Tyrosine kinases and E-LTP

NMDA receptors, which are heteromeric channels that consist of NR1 and NR2A–D subunits, form complexes in the PSD with other proteins such as PSD95, Ca2+–calmodulin, SAP102, α-actinin and the tyrosine-kinase family members2. The NR2A and NR2B subunits are subject to tyrosine-residue phosphorylation, and infusion of tyrosine kinases potentiates the current through NR1–NR2A or NR1–NR2B recombinant channels by phosphorylation of intracellular, C-terminal tyrosine residues, thereby relieving a

Phosphorylation and modulation of AMPA receptors: Ca2+-dependent kinases in E-LTP

Given that the induction of LTP in CA1 is blocked by general inhibitors of Ser/Thr protein kinases or by postsynaptic chelation of Ca2+, a potential role for Ca2+-dependent protein kinases, such as Ca2+/calmodulin-dependent protein kinase II (CaMKII) or PKC, or both, is reasonable. Infusion of peptide inhibitors of either of these two protein kinases or of calmidazolium, a calmodulin (CaM) antagonist, into pyramidal neurons blocks induction of LTP, indicating a postsynaptic locus for their

Regulation of protein phosphatases during E-LTP

Neurons not only have high levels of many protein kinases, but they are also rich sources for many protein phosphatases, including protein phosphatases 1, 2A (PP1, PP2A) and 2B (PP2B or calcineurin). PP1 and PP2A are very effective at dephosphorylating Thr286 in CaMKII, thereby reversing its constitutive activity to basal levels. They are also able to dephosphorylate Ser831 of GluR1 in vitro (A. Barria and T.R. Soderling, unpublished observations). There is significant PP1 and PP2A in the PSD,

The ‘silent synapse’ hypothesis in E-LTP

The fact that only 60% of potentiated CA1 neurons show an increase in AMPA-receptor channel unitary conductance38 suggests that mechanisms in addition to phosphorylation of AMPA receptors by CaMKII are also operative. There is extensive evidence for the ‘silent synapse’ hypothesis47, 48, which states that prior to induction of LTP some synapses do not have functional AMPA receptors, whereas after LTP induction they exhibit AMPA-receptor-mediated currents. This might result from recruitment of

Concluding remarks

Studies over the past five years have begun to map out some of the signal-transduction pathways that are used in modulating synaptic strength at the postsynaptic locus in CA1 hippocampal neurons. It is clear that phenomena such as LTP, which might contribute to learning and memory, use multiple mechanisms, many of which involve protein phosphorylation. These studies have emphasized roles in E-LTP for the transient potentiation of NMDA receptors, through tyrosine-residue phosphorylation, in

References (60)

  • A.L. Mammen

    Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II

    J. Biol. Chem.

    (1997)
  • Z. Jia

    Enhanced LTP in mice deficient in the AMPA receptor GluR2

    Neuron

    (1996)
  • K.W. Roche

    Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit

    Neuron

    (1996)
  • K. Kameyama

    Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression

    Neuron

    (1998)
  • J.T. Isaac

    Evidence for silent synapses: implications for the expression of LTP

    Neuron

    (1995)
  • J.E. Pessin

    Molecular basis of insulin-stimulated GLUT4 vesicle trafficking

    J. Biol. Chem.

    (1999)
  • P. Osten

    The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs

    Neuron

    (1998)
  • A. Nishimune

    NSF binding to GluR2 regulates synaptic transmission

    Neuron

    (1998)
  • I. Song

    Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors

    Neuron

    (1998)
  • D.A. Frank et al.

    CREB: a mediator of long-term memory from mollusks to mammals

    Cell

    (1994)
  • L. Wu

    CPEB-mediated cytoplasmic polyadenylation and the regulation of experience-dependent translation of alpha-CaMKII mRNA at synapses

    Neuron

    (1998)
  • U. Frey et al.

    Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation

    Trends Neurosci.

    (1998)
  • T.V.P. Bliss et al.

    Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

    J. Phyiol.

    (1973)
  • C.H. Bailey

    Toward a molecular definition of long-term memory storage

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • A.S. Nayak

    Ca2+/calmodulin-dependent protein kinase II phosphorylation of the presynaptic protein synapsin I is persistently increased during long-term potentiation

    Proc. Natl. Acad. Sci .U. S. A.

    (1996)
  • F. Zheng

    Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition

    Nat. Neurosci.

    (1998)
  • Y.M. Lu

    Src activation in the induction of long-term potentiation in CA1 hippocampal neurons

    Science

    (1998)
  • A. Barria

    Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation

    Science

    (1997)
  • E. Klann

    Mechanism of protein kinase C activation during the induction and maintenance of long-term potentiation probed using a selective peptide substrate

    Proc. Natl. Acad. Sci. U. S. A.

    (1993)
  • T.C. Sactor

    Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation

    Proc. Natl. Acad. Sci. U. S. A.

    (1993)
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