Protein Phosphorylation and Long‐term Synaptic Plasticity


Learning and memory are complex biological processes that utilize multiple mechanisms in the brain. Some of these mechanisms, which involve phosphorylation of key regulatory brain proteins, have been identified.

Keywords: learning and memory; synaptic plasticity; protein phosphorylation

Figure 1.

Role of protein phosphatases in hippocampal long‐term depression (LTD). Low‐frequency stimulation of afferent pathways will produce a small and sustained increase in postsynaptic Ca2+ that selectively activates calcineurin (CaN) and triggers LTD. Dephosphorylation of inhibitor 1 (I‐1) by CaN causes activation of protein phosphatase 1 (PP1). Calcium/calmodulin‐dependent protein kinase II (CaM‐KII) is dephosphorylated by PP1, reversing its basal Ca2+/calmodulin‐independent activity. Also, PP1 might dephosphorylate basally phosphorylated α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole propionate‐type glutamate receptors (AMPA‐Rs).

Figure 2.

Protein phosphorylation during long‐term potentiation (LTP). High‐frequency stimulation will produce a large increase in postsynaptic Ca2+. This Ca2+, complexed with calmodulin (CaM), activates calcium/calmodulin‐dependent protein kinase II (CaM‐KII) and allows its autophosphorylation on (Thr286). Constitutively active CaM‐KII phosphorylates α‐ (AMPA‐Rs) at serine 831 (Ser831) in the (GluR1) subunit, increasing AMPA‐R conductance. Other protein kinases are also activated. Protein kinase C (PKC) can phosphorylate the same site in GluR1 as CaM‐KII, and cAMP‐dependent protein kinase (PKA) can turn off protein phosphatases by phosphorylating (I‐1). Expression of late‐phase LTP (L‐LTP) requires gene transcription and protein synthesis. Transcription factor cAMP‐responsive element‐binding protein (CREB) is turned on by phosphorylation at Ser133 by PKA or CaM‐KIV.



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Further Reading

Bliss TV and Collingridge GL (1993) A synaptic model of memory: long‐term potentiation in the hippocampus. Nature 361: 31–39.

Fukunaga K, Muller D and Miyamoto E (1996) CaM kinase II in long‐term potentiation. Neurochemistry International 28: 343–358.

Lisman J, Malenka RC, Nicoll RA and Malinow R (1997) Learning mechanisms: the case for CaM‐KII. Science 276: 2001–2002.

Malenka R (1994) Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78: 535–538.

Nicoll RA and Malenka RC (1995) Contrasting properties of two forms of long‐term potentiation in the hippocampus. Nature 377: 115–118.

Schulman H (1995) Protein phosphorylation in neuronal plasticity and gene expression. Current Opinion in Neurobiology 5: 375–381.

Silva A, Kogan J, Frankland P and Kida S (1998) CREB and memory. Annual Review of Neuroscience 21: 127–148.

Soderling TR (1995) Calcium‐dependent protein kinases in learning and memory. Advances in Second Messenger and Phosphoprotein Research 30: 175–189.

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Barria, A, Derkach, V, and Soderling, TR(Apr 2001) Protein Phosphorylation and Long‐term Synaptic Plasticity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0000262]