Abstract
Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1−/− mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1−/− or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB. Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.
| Original language | English |
|---|---|
| Pages (from-to) | 5437-5447 |
| Number of pages | 11 |
| Journal | Journal of Neuroscience |
| Volume | 36 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - May 18 2016 |
Fingerprint
Keywords
- Dendritic spines
- Glutamatergic transmission
- Hippocampus
- NMDA receptors
- Pin1
- PSD-95
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Pin1 modulates the synaptic content of NMDA receptors via prolyl-isomerization of PSD-95. / Antonelli, Roberta; de Filippo, Roberto; Middei, Silvia; Stancheva, Stefka; Pastore, Beatrice; Ammassari-Teule, Martine; Barberis, Andrea; Cherubini, Enrico; Zacchi, Paola.
In: Journal of Neuroscience, Vol. 36, No. 20, 18.05.2016, p. 5437-5447.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pin1 modulates the synaptic content of NMDA receptors via prolyl-isomerization of PSD-95
AU - Antonelli, Roberta
AU - de Filippo, Roberto
AU - Middei, Silvia
AU - Stancheva, Stefka
AU - Pastore, Beatrice
AU - Ammassari-Teule, Martine
AU - Barberis, Andrea
AU - Cherubini, Enrico
AU - Zacchi, Paola
PY - 2016/5/18
Y1 - 2016/5/18
N2 - Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1−/− mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1−/− or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB. Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.
AB - Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1−/− mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1−/− or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB. Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.
KW - Dendritic spines
KW - Glutamatergic transmission
KW - Hippocampus
KW - NMDA receptors
KW - Pin1
KW - PSD-95
UR - http://www.scopus.com/inward/record.url?scp=84969234387&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84969234387&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3124-15.2016
DO - 10.1523/JNEUROSCI.3124-15.2016
M3 - Article
VL - 36
SP - 5437
EP - 5447
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 20
ER -