Impaired NMDA Receptor-Mediated Postsynaptic Function and Blunted NMDA Receptor-Dependent Persistent Pain in Mice Lacking Postsynaptic Density-93 Protein

Tao, Yuan Xiang; Rumbaugh, Gavin; Wang, Guo Du; Petralia, Ronald S.; Zhao, Cheng; Kauer, Frederick; Tao, Feng; Zhuo, Min; Wenthold, Robert J.; Raja, Srinivasa N.; Huganir, Richard L.; Bredt, David S.; Johns, Roger A.

doi:10.1523/jneurosci.23-17-06703.2003

Cited by 136 publications

(161 citation statements)

References 66 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…Aside from promoting cell surface channel clustering, we find that the association between Kir2.1 and PSD-93␦ profoundly suppresses the rate of Kir2.1 internalization, effectively stabilizing the channel in the membrane. A role for MAGUKs in the regulation of channel and receptor surface expression is supported by the finding that deletion of the C-terminal PDZ binding motif of NR2B subunits increases the rate of NMDAR internalization in neurons (34), and by a recent study that shows a reduction of surface NR2A and NR2B expression in spinal dorsal horn neurons of PSD-93 knockout mice (39). The rate of internalization of Kv1.4 and Kv4.2 channels is also reduced when coexpressed with PSD-95 (33,43), and at least in the case of Kv1.4, surface stabilization seems to intimately linked with channel clustering, since PSD-95 mutants that bind but do not cluster Kv1.4 allow rapid channel endocytosis (33).…”

Section: Discussionmentioning

confidence: 95%

“…Abundant PSD-93 expression of unknown isoforms has been reported previously in the superficial dorsal horn of spinal cord, a primary center for the transmission and processing of pain signals (39,40). Here PSD-93 plays a familiar role in targeting N-methyl-D-asparate receptors (NMDARs) to postsynaptic membranes.…”

Section: Discussionmentioning

confidence: 99%

“…Here PSD-93 plays a familiar role in targeting N-methyl-D-asparate receptors (NMDARs) to postsynaptic membranes. Genetic deletion of PSD-93 lowers the surface expression of NMDAR subunits NR2A and NR2B in dorsal horn neurons and significantly reduces NMDAR-dependent persistent inflammatory or nerve injury-induced neuropathic pain (39). A variant of PSD-93 that is expressed predominantly in spinal cord is therefore an attractive potential target for the treatment of chronic pain.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

An Alternatively Spliced Isoform of PSD-93/Chapsyn 110 Binds to the Inwardly Rectifying Potassium Channel, Kir2.1

Leyland¹,

Dart

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Inwardly rectifying potassium (Kir) channels are prime determinants of resting membrane potential in neurons. Their subcellular distribution and surface density thus help shape neuronal excitability, yet mechanisms governing the membrane targeting and localization of Kir channels are poorly understood. Here we report a direct interaction between the strong inward rectifier, Kir2.1, and a recently identified splice variant of postsynaptic density-93 (PSD-93), a protein involved the subcellular targeting of ion channels and glutamate receptors at excitatory synapses. Yeast two-hybrid screening of a human brain cDNA library using the carboxyl terminus of Kir2.1 as bait yielded cDNA encoding the first two PDZ domains of PSD-93, but with an extended N-terminal region that diverged from other PSD-93 isoforms. This clone represented the human homologue of the mouse PSD-93 splice variant, PSD-93␦. Reverse transcription-polymerase chain reaction analysis showed diffuse low level PSD-93␦ expression throughout the brain, with significantly higher levels in spinal cord. In vitro binding studies revealed that a type I PDZ recognition motif at the extreme C terminus of the Kir2.1 mediates interaction with all three PDZ domains of PSD-93␦, and association between Kir2 channels and PSD-93␦ was confirmed further by the ability of antiKir2.1 antibodies to coimmunoprecipitate PSD-93␦ from rat spinal cord lysates. Functionally, coexpression of Kir2.1 and PSD-93␦ had no discernible effect upon channel kinetics but resulted in cell surface Kir2.1 clustering and suppression of channel internalization. We conclude that PSD-93␦ is potentially an important regulator of the spatial and temporal distribution of Kir2 channels within neuronal membranes of the central nervous system.Inwardly rectifying potassium channels comprise a family of integral membrane proteins whose diverse cellular functions include maintenance of the resting membrane potential, control of neuronal excitability and heart rate, and potassium homeostasis (1-3). Underlying these functions is the property of inward rectification, the ability to allow potassium to move easily into the cell at membrane potentials negative to the potassium equilibrium potential (E K ) but to restrict potassium outflow at potentials positive to E K . This asymmetry in the current-voltage relation results from the channel's susceptibility to voltage-dependent block by intracellular polyamines and magnesium ions (4, 5) and ensures that, while being extremely active around E K , they pass little or no current at membrane potentials positive to Ϫ40 mV. Thus, Kir 1 channels maintain a tight control on the resting membrane potential but close in the face of significant membrane depolarization (such as that generated by the cardiac or neuronal action potential) to protect the cell from excessive K ϩ loss. This pivotal role in the regulation of the membrane potential makes Kir channels attractive candidates for modulation by neurotransmitters and hormones, since even small fluctuations in Kir channe...

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

An Alternatively Spliced Isoform of PSD-93/Chapsyn 110 Binds to the Inwardly Rectifying Potassium Channel, Kir2.1

Leyland¹,

Dart

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We observed similar distribution patterns for both native and ␤-neurexin-induced PSD-95 and NR2A clusters; NMDARs are present at some but not all PSD-95 clusters. It is possible that other membrane-associated guanylate kinase family members, such as PSD-93 or SAP-102 (30,31), mediate neurexin-induced and normal synaptic clustering of NMDARs.…”

Section: Discussionmentioning

confidence: 99%

Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter

Nam

Chen

2005

Proc. Natl. Acad. Sci. U.S.A.

292

275

View full text Add to dashboard Cite

Presynaptic and postsynaptic differentiation occurs at axodendritic contacts between CNS neurons. Synaptic adhesion mediated by synaptic cell adhesion molecule (SynCAM) and ␤-neurexins͞neu-roligins triggers presynaptic differentiation. The signals that trigger postsynaptic differentiation are, however, unknown. Here we report that ␤-neurexin expressed in nonneuronal cells induced postsynaptic density (PSD)-95 clustering in contacting dendrites of hippocampal neurons. The effect is specific to ␤-neurexin and was not observed with other synaptic cell adhesion molecules such as N-cadherin or SynCAM. NMDA receptors, but not ␣-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs), were recruited to this ␤-neurexin-induced PSD-95 scaffold. Remarkably, AMPARs were inserted into this scaffold upon glutamate application or expression of a constitutively active form of calmodulin kinase II in neurons. Expression of a dominant-negative neuroligin-1 in cultured neurons markedly reduced the sizes and densities of PSD-95 puncta and AMPAR clusters. In addition, excitatory, but not inhibitory, synaptic functions were impaired in these neurons, confirming that PSD-95͞neuroligin-1 interaction is involved in postsynaptic assembly at glutamatergic synapses. These results demonstrate that postsynaptic assembly of the glutamatergic synapse may be initiated by presynaptic ␤-neurexin and that glutamate release also is required for maturation of synapses.␤-neurexin ͉ glutamatergic synapse formation ͉ synaptogenesis I nteractions between presynaptic and postsynaptic neurons are essential for synapse formation (1-5). At glutamatergic synapses in the mammalian CNS, presynaptic differentiation appears to be induced by synaptic adhesion molecules, such as synaptic cell adhesion molecule (SynCAM) and neuroligins (6-8). Mechanisms underlying CNS postsynaptic differentiation are unclear. Although major components of the postsynaptic density (PSD) have been identified, and the sequence of their assembly at nascent glutamatergic synapses has been delineated (1, 3), the axonal signals that induce postsynaptic assembly are still unknown. Recent studies indicate that ␤-neurexin is synaptically localized and is the axonal receptor of neuroligin-1 (NL1) (6). In addition, NL1 directly interacts with PSD-95 through its C-terminal PDZ-binding motif (9), an interaction that modulates excitatory postsynaptic formation (10-12). These findings suggest that ␤-neurexin͞NL1 interaction may initiate postsynaptic differentiation by recruiting postsynaptic scaffolding proteins such as PSD-95.Another potential player in postsynaptic differentiation is neurotransmitter. Observations from Munc18-1-knockout mice suggest that the initial assembly of the synapse, evaluated with ultrastructural morphology and localization of presynaptic proteins, may proceed without neurotransmitter release. However, because postsynaptic receptor localization and function were not evaluated in these mice, whether transmitter release is required for a fully functional postsyn...

show abstract

“…12,19,23,69,70 Abnormal expression of these proteins could affect NMDA receptor function. Interestingly, previous studies have reported transcript expression for these PSD molecules of opposite polarity, possibly depending on the neuroanatomical structure and subject characteristics of the cohort studied.…”

Section: Discussionmentioning

confidence: 99%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

View full text Add to dashboard Cite

Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

show abstract

Impaired NMDA Receptor-Mediated Postsynaptic Function and Blunted NMDA Receptor-Dependent Persistent Pain in Mice Lacking Postsynaptic Density-93 Protein

Cited by 136 publications

References 66 publications

An Alternatively Spliced Isoform of PSD-93/Chapsyn 110 Binds to the Inwardly Rectifying Potassium Channel, Kir2.1

An Alternatively Spliced Isoform of PSD-93/Chapsyn 110 Binds to the Inwardly Rectifying Potassium Channel, Kir2.1

Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

Contact Info

Product

Resources

About