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A role for sorting nexin 27 in AMPA receptor trafficking.

Loo LS, Tang N, Al-Haddawi M, Dawe GS, Hong W - Nat Commun (2014)

Bottom Line: Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors.Impairment of SNX27 prevents LTP and associated trafficking of AMPARs.These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Molecular and Cell Biology, Singapore 138673, Singapore [2] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore.

ABSTRACT
Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down's syndrome. However, the precise molecular role of SNX27 in GluA1 trafficking is unclear. Here we report that SNX27 is enriched in dendrites and spines, along with recycling endosomes. Significantly, the mobilization of SNX27 along with recycling endosomes into spines was observed. Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors. Impairment of SNX27 prevents LTP and associated trafficking of AMPARs. These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

No MeSH data available.


Related in: MedlinePlus

GluN1 expression in wild type and SNX27−/− mice.(a) GluN1 amounts in synaptosomes and PSD fractions derived from wild type and SNX27−/− hippocampus. (b) Graph shows the GluN1 levels in synaptosomes and PSD fractions of SNX27−/− hippocampus relative to wild-type hippocampus. n=3; **indicates P<0.05, unpaired t-test; error bars=s.e.m.
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f6: GluN1 expression in wild type and SNX27−/− mice.(a) GluN1 amounts in synaptosomes and PSD fractions derived from wild type and SNX27−/− hippocampus. (b) Graph shows the GluN1 levels in synaptosomes and PSD fractions of SNX27−/− hippocampus relative to wild-type hippocampus. n=3; **indicates P<0.05, unpaired t-test; error bars=s.e.m.

Mentions: Since NMDA receptor activation is required in Gly-induced recycling, we need to be convinced that impaired recycling observed in the knockouts is due to the absence of SNX27 and not the result of drastic alteration in endogenous GluN1 expression in the SNX27−/− neurons. We analysed GluN1 expression levels in the hippocampus of wild type and SNX27−/− mice. Our blotting results show similar expression of GluN1 in the synaptosome and Triton-insoluble (PSD) fraction (Fig. 6). Quantitative analysis showed that there was a slight decline in GluN1 expression in the synaptosome and PSD fraction of the SNX27 −/− hippocampus compared with wild type (82% and 85% respectively; n=3; P<0.05, Student’s t-test). However, it is unlikely that this small difference in GluN1 levels could account for the large impairment in transferrin recycling observed here. Therefore, we conclude that overall transferrin transport from recycling endosomes to plasma membrane is significantly compromised in SNX27-deficient neurons.


A role for sorting nexin 27 in AMPA receptor trafficking.

Loo LS, Tang N, Al-Haddawi M, Dawe GS, Hong W - Nat Commun (2014)

GluN1 expression in wild type and SNX27−/− mice.(a) GluN1 amounts in synaptosomes and PSD fractions derived from wild type and SNX27−/− hippocampus. (b) Graph shows the GluN1 levels in synaptosomes and PSD fractions of SNX27−/− hippocampus relative to wild-type hippocampus. n=3; **indicates P<0.05, unpaired t-test; error bars=s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921469&req=5

f6: GluN1 expression in wild type and SNX27−/− mice.(a) GluN1 amounts in synaptosomes and PSD fractions derived from wild type and SNX27−/− hippocampus. (b) Graph shows the GluN1 levels in synaptosomes and PSD fractions of SNX27−/− hippocampus relative to wild-type hippocampus. n=3; **indicates P<0.05, unpaired t-test; error bars=s.e.m.
Mentions: Since NMDA receptor activation is required in Gly-induced recycling, we need to be convinced that impaired recycling observed in the knockouts is due to the absence of SNX27 and not the result of drastic alteration in endogenous GluN1 expression in the SNX27−/− neurons. We analysed GluN1 expression levels in the hippocampus of wild type and SNX27−/− mice. Our blotting results show similar expression of GluN1 in the synaptosome and Triton-insoluble (PSD) fraction (Fig. 6). Quantitative analysis showed that there was a slight decline in GluN1 expression in the synaptosome and PSD fraction of the SNX27 −/− hippocampus compared with wild type (82% and 85% respectively; n=3; P<0.05, Student’s t-test). However, it is unlikely that this small difference in GluN1 levels could account for the large impairment in transferrin recycling observed here. Therefore, we conclude that overall transferrin transport from recycling endosomes to plasma membrane is significantly compromised in SNX27-deficient neurons.

Bottom Line: Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors.Impairment of SNX27 prevents LTP and associated trafficking of AMPARs.These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Molecular and Cell Biology, Singapore 138673, Singapore [2] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore.

ABSTRACT
Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down's syndrome. However, the precise molecular role of SNX27 in GluA1 trafficking is unclear. Here we report that SNX27 is enriched in dendrites and spines, along with recycling endosomes. Significantly, the mobilization of SNX27 along with recycling endosomes into spines was observed. Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors. Impairment of SNX27 prevents LTP and associated trafficking of AMPARs. These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

No MeSH data available.


Related in: MedlinePlus