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Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5.

Hou H, Sun L, Siddoway BA, Petralia RS, Yang H, Gu H, Nairn AC, Xia H - J. Cell Biol. (2013)

Bottom Line: The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown.Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons.Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience Center, LSU Health Science Center, New Orleans, LA 70112.

ABSTRACT
The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown. We find that synaptic N-methyl-D-aspartate (NMDA) receptor stimulation in neurons leads to activation of PP1 through a mechanism involving inhibitory phosphorylation at Thr320 by Cdk5. Synaptic stimulation led to proteasome-dependent degradation of the Cdk5 regulator p35, inactivation of Cdk5, and increased auto-dephosphorylation of Thr320 of PP1. We also found that neither inhibitor-1 nor calcineurin were involved in the control of PP1 activity in response to synaptic NMDA receptor stimulation. Rather, the PP1 regulatory protein, inhibitor-2, formed a complex with PP1 that was controlled by synaptic stimulation. Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons. Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity.

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Model. Calcium influx via NMDA receptors will lead to p35 degradation that in turn leads to decreased Cdk5 activity. Decreased Cdk5 activity will lead to increased PP1 activity (via PP1 auto-dephosphorylation at T320) that in turn will lead to dephosphorylation of I-2 at T72, resulting in PP1 access to other substrates, eventually leading to synaptic depression (dotted lines). The PP1–I-2 complex is probably targeted to spines via interaction with neurabin, and this part of the proposed mechanism for I-2 function has been encircled with a dotted box, indicating speculation.
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fig7: Model. Calcium influx via NMDA receptors will lead to p35 degradation that in turn leads to decreased Cdk5 activity. Decreased Cdk5 activity will lead to increased PP1 activity (via PP1 auto-dephosphorylation at T320) that in turn will lead to dephosphorylation of I-2 at T72, resulting in PP1 access to other substrates, eventually leading to synaptic depression (dotted lines). The PP1–I-2 complex is probably targeted to spines via interaction with neurabin, and this part of the proposed mechanism for I-2 function has been encircled with a dotted box, indicating speculation.

Mentions: Given the known role of PP1 in LTD, the fact that I-2 KD leads to an increase in pT320 levels in PP1 indicative of reduced PP1 activity, and the fact that synaptic NMDA receptor signaling regulates I-2 T72 phosphorylation, the results support a role for I-2 in regulation of PP1 by synaptic NMDA receptor signaling. Moreover, although we cannot formally rule out the possibility that I-2’s role in LTD is independent of its PP1 regulatory function, again given the known role of PP1 in LTD, our data are consistent with a model that PP1 in the I-2 complex is inhibited by Cdk5-dependent phosphorylation at T320. The phosphorylation of T320 is balanced by auto-dephosphorylation. After NMDA receptor opening, Cdk5 activity is decreased as a consequence of proteasomal degradation of p35, thus tilting the balance of phosphorylation/dephosphorylation in favor of reduced pT320 PP1, and PP1 activation (Fig. 7). The regulation of pT320 takes place in the PP1–I-2 complex. Within this complex, NMDA receptor stimulation also leads to dephosphorylation of T72, presumably as a result of increased PP1 activity. Based on results from analysis of a T72A–I-2 mutant protein, the dephosphorylation of T72 appears to be responsible for increasing the association of PP1 and I-2. In this process, I-2 does not function necessarily as a PP1 inhibitor, but rather as an accessory/regulatory PP1 binding protein. In support of this, I-2 KD in resting neurons led to increased PP1 inhibitory phosphorylation at T320 without any effect on PP1 levels, indicative of decreased PP1 activity, which is the opposite of what would be expected if I-2 was simply an inhibitor of PP1. This result is consistent with yeast studies where loss of function of Glc8, a yeast homologue of I-2, leads to decreased PP1 activity where Glc8 was interpreted as a functional PP1 activator (Tung et al., 1995; Nigavekar et al., 2002).


Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5.

Hou H, Sun L, Siddoway BA, Petralia RS, Yang H, Gu H, Nairn AC, Xia H - J. Cell Biol. (2013)

Model. Calcium influx via NMDA receptors will lead to p35 degradation that in turn leads to decreased Cdk5 activity. Decreased Cdk5 activity will lead to increased PP1 activity (via PP1 auto-dephosphorylation at T320) that in turn will lead to dephosphorylation of I-2 at T72, resulting in PP1 access to other substrates, eventually leading to synaptic depression (dotted lines). The PP1–I-2 complex is probably targeted to spines via interaction with neurabin, and this part of the proposed mechanism for I-2 function has been encircled with a dotted box, indicating speculation.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3824016&req=5

fig7: Model. Calcium influx via NMDA receptors will lead to p35 degradation that in turn leads to decreased Cdk5 activity. Decreased Cdk5 activity will lead to increased PP1 activity (via PP1 auto-dephosphorylation at T320) that in turn will lead to dephosphorylation of I-2 at T72, resulting in PP1 access to other substrates, eventually leading to synaptic depression (dotted lines). The PP1–I-2 complex is probably targeted to spines via interaction with neurabin, and this part of the proposed mechanism for I-2 function has been encircled with a dotted box, indicating speculation.
Mentions: Given the known role of PP1 in LTD, the fact that I-2 KD leads to an increase in pT320 levels in PP1 indicative of reduced PP1 activity, and the fact that synaptic NMDA receptor signaling regulates I-2 T72 phosphorylation, the results support a role for I-2 in regulation of PP1 by synaptic NMDA receptor signaling. Moreover, although we cannot formally rule out the possibility that I-2’s role in LTD is independent of its PP1 regulatory function, again given the known role of PP1 in LTD, our data are consistent with a model that PP1 in the I-2 complex is inhibited by Cdk5-dependent phosphorylation at T320. The phosphorylation of T320 is balanced by auto-dephosphorylation. After NMDA receptor opening, Cdk5 activity is decreased as a consequence of proteasomal degradation of p35, thus tilting the balance of phosphorylation/dephosphorylation in favor of reduced pT320 PP1, and PP1 activation (Fig. 7). The regulation of pT320 takes place in the PP1–I-2 complex. Within this complex, NMDA receptor stimulation also leads to dephosphorylation of T72, presumably as a result of increased PP1 activity. Based on results from analysis of a T72A–I-2 mutant protein, the dephosphorylation of T72 appears to be responsible for increasing the association of PP1 and I-2. In this process, I-2 does not function necessarily as a PP1 inhibitor, but rather as an accessory/regulatory PP1 binding protein. In support of this, I-2 KD in resting neurons led to increased PP1 inhibitory phosphorylation at T320 without any effect on PP1 levels, indicative of decreased PP1 activity, which is the opposite of what would be expected if I-2 was simply an inhibitor of PP1. This result is consistent with yeast studies where loss of function of Glc8, a yeast homologue of I-2, leads to decreased PP1 activity where Glc8 was interpreted as a functional PP1 activator (Tung et al., 1995; Nigavekar et al., 2002).

Bottom Line: The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown.Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons.Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience Center, LSU Health Science Center, New Orleans, LA 70112.

ABSTRACT
The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown. We find that synaptic N-methyl-D-aspartate (NMDA) receptor stimulation in neurons leads to activation of PP1 through a mechanism involving inhibitory phosphorylation at Thr320 by Cdk5. Synaptic stimulation led to proteasome-dependent degradation of the Cdk5 regulator p35, inactivation of Cdk5, and increased auto-dephosphorylation of Thr320 of PP1. We also found that neither inhibitor-1 nor calcineurin were involved in the control of PP1 activity in response to synaptic NMDA receptor stimulation. Rather, the PP1 regulatory protein, inhibitor-2, formed a complex with PP1 that was controlled by synaptic stimulation. Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons. Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity.

Show MeSH
Related in: MedlinePlus