The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol‐3‐kinase recruitment

Arbuckle, Margaret I.; Komiyama, Noboru H.; Delaney, Ada; Garry, Emer M.; Rosie, Roberta; Allchorne, Andrew; Forsyth, Lynsey H; Bence, Matthew; Carlisle, Holly J.; O’Dell, Thomas J.; Mitchell, Rory; Fleetwood-Walker, Susan M.; Grant, Seth G. N.

doi:10.1038/embor.2010.63

Cited by 26 publications

(22 citation statements)

References 22 publications

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“…Class I isoforms have been studied most extensively: PI3Kα, PI3Kβ and PI3Kδ are activated by receptor tyrosine-kinases [23], while PI3Kγ is activated by G-protein-coupled receptors (GPCRs), including chemokine receptors, to regulate cellular functions such as cell survival, proliferation, migration and adhesion [39]. Class II and III PI3K differ from class I in structure and regulation and will not be discussed here, although one class II isoform has been implicated in spinal pain processing [2]. PI3Kα and PI3Kβ are ubiquitously expressed by most or all cell types [50], while PI3Kδ and PI3Kγ are predominantly found in cells with hematopoietic [39] and endothelial [38] lineage.…”

Section: Introductionmentioning

confidence: 99%

Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: Potential roles in acute inflammatory pain

Leinders

Koehrn

Bartók

et al. 2014

Pain

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PI3-kinases (PI3Ks) participate in nociception within spinal cord, dorsal root ganglion (DRG) and peripheral nerves. To extend our knowledge, we immunohistochemically stained for each of the four Class I PI3K isoforms along with several cell specific markers within lumbar spinal cord, DRG and sciatic nerve of naïve rats. Intrathecal and intraplantar isoform specific antagonists were given as pre-treatments before intraplantar carrageenan; pain behavior was then assessed over time. The α-isoform was localized to central terminals of primary afferent fibers in spinal cord laminae IIi-IV as well as to neurons in ventral horn and DRG. The PI3Kβ isoform was the only Class I isoform seen in dorsal horn neurons, it was also observed in DRG, Schwann cells and axonal paranodes. The δ-isoform was found in spinal cord white matter oligodendrocytes and radial astrocytes, while the γ-isoform was seen in a subpopulation of IB4-positive DRG neurons. No isoform co-localized with microglial markers or satellite cells in naïve tissue. Only the PI3Kβ antagonist, but none of the other antagonists, had anti-allodynic effects when administered intrathecally; coincident with reduced pain behavior, this agent completely blocked paw carrageenan-induced dorsal horn 2-amino-3-(3-hydroxy-5-methylisoxazol- 4-yl) propanoic acid (AMPA) receptor trafficking to plasma membranes. Intraplantar administration of the γ-antagonist prominently reduced pain behavior. These data suggest that each isoform displays specificity with regard to neuronal type as well as to specific tissues. Furthermore, each PI3K isoform has a unique role in development of nociception and tissue inflammation.

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Section: Introductionmentioning

confidence: 99%

Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: Potential roles in acute inflammatory pain

Leinders

Koehrn

Bartók

et al. 2014

Pain

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“…This tryptophan is conserved in all the PSD-95 MAGUKs. Moreover, when mutated it abrogated the recruitment of phosphatidylinositol 3-kinase-C2␣ to the SH3-binding site of PSD-95 (32). Thus, the W470L point mutation was introduced into full-length PSD-95, and the interactions between wild-type and PSD-95 W470L and wild-type and NR2A truncated and mutated C-terminal tails were investigated in parallel by yeast two-hybrid interaction assays.…”

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confidence: 99%

Identification of N-Methyl-d-aspartic Acid (NMDA) Receptor Subtype-specific Binding Sites That Mediate Direct Interactions with Scaffold Protein PSD-95

Cousins

Stephenson

2012

Journal of Biological Chemistry

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Background: NMDA receptors are organized via scaffold proteins into macromolecular signaling complexes at synapses. Results: Novel binding sites that govern NMDA receptor/scaffold protein association have been delineated. Conclusion: The scaffold, PSD-95, binds to two sites that differ between NMDA receptor NR2A and NR2B subunits. Significance: The molecular basis of protein/protein interactions that contribute to organization of synaptic signaling complexes is extended and enhanced.

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“…6B). Mice carrying a complete LoF mutation in PSD95 (PSD-95-GK) showed major NCRR phenotypes, whereas a point mutation (PSD-95-SH3) 43 introducing a single amino acid change in the binding site of the SH3 domain had no significant phenotype (Fig. 6B).…”

Section: Vertebrate Proteome Evolution Generated Response Complexitymentioning

confidence: 99%

A combinatorial postsynaptic molecular mechanism converts patterns of nerve impulses into the behavioral repertoire

Kopanitsa

Lagemaat

Afinowi

et al. 2018

Preprint

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How is the information encoded within patterns of nerve impulses converted into diverse behavioral responses? To address this question, we conducted the largest genetic study to date of the electrophysiological and behavioral properties of synapses.Postsynaptic responses to elementary patterns of activity in the hippocampal CA1 region were measured in 58 lines of mice carrying mutations in the principal classes of excitatory postsynaptic proteins. A combinatorial molecular mechanism was identified in which distinct subsets of proteins amplified or attenuated responses across timescales from milliseconds to an hour. The same mechanism controlled the diversity and magnitude of innate and learned behavioral responses. PSD95 supercomplex proteins were central components of this synaptic machinery. The capacity of vertebrate synapses to compute activity patterns increased with genome evolution and is impaired by disease-relevant mutations. We propose that this species-conserved molecular mechanism converts the temporally encoded information in nerve impulses into the repertoire of innate and learned behavior.

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The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol‐3‐kinase recruitment

Cited by 26 publications

References 22 publications

Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: Potential roles in acute inflammatory pain

Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: Potential roles in acute inflammatory pain

Identification of N-Methyl-d-aspartic Acid (NMDA) Receptor Subtype-specific Binding Sites That Mediate Direct Interactions with Scaffold Protein PSD-95

A combinatorial postsynaptic molecular mechanism converts patterns of nerve impulses into the behavioral repertoire

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