Trends in Neurosciences
ReviewPostsynaptic protein phosphorylation and LTP
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 They are also able to dephosphorylate Ser831 of GluR1 in vitro (A. Barria and T.R. Soderling, unpublished observations).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
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