Phosphorylation

Phosphorylation modulates the function of AMPA, kainate, and NMDA receptors (summarized in ref. 3) and is associated with synaptic plasticity. For example, phosphorylation of GluRl at Ser831 by calcium calmodulin kinase II (CAMKII) increases AMPA receptor-mediated current flow and is one of the mechanisms by which long-term potentiation (LTP) occurs. In contrast, during long-term depression, GluRl is dephosphorylated at protein kinase A (PKA) phosphorylation site, Ser845, decreasing the opening probablility of AMPA receptors. The GluR2-4 subunits do not contain these two phospho-rylatable serines. Instead, GluR2 can be phosphorylated at Ser880 by PKC, which is located within the sequence critical for PDZ domain binding. GluR2 phosphorylation at Ser880 decreases GRIP1 binding (66,67; see Section 3.6). Moreover, Ser842 of GluR4 can be phosphorylated by PKA, PKC, and CAMKII, and Thr830 is a potential PKC phosphorylation site (68).

Phosphorylation of NMDA receptors at several sites increases ionic currents through activated receptors. PKC phosphorylation increases the opening probability of NMDA receptors (69). However, it is not clear whether the identified PKC phosphorylation sites, Ser890, Ser896, and Thr879 in the alternatively spliced C1 domain of NR1, confer the effect (70). Phosphorylation of Ser890 also inhibits receptor clustering. Little is known about NMDA receptor phosphorylation by PKA and CAMKII, although at least two sites can be phosphorylated: Ser897 in the C1 domain of NR1 by PKA and Ser1303 in NR2B by CAMKII. Tyrosine phosphorylation of NMDA receptors is another way to increase NMDA receptor currents. The endogenous tyrosine kinase Src phosphory-lates three C-terminal tyrosines (Y1105, Y1267, and Y1387) in NR2A, which reduces Zn2+ blockade, thereby potentiating the receptor (71; see Section 4.3.1.). The potentiation of NMDA receptor currents by Src is one mechanism leading to LTP in CA1 pyramidal cells (72). Another tyrosine kinase that phosphorylates NR2A and NR2B is Fyn. Fyn knock-out mice are impaired in LTP and spatial learning (73).

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