NMDA receptor subunits in the postsynaptic density of rat brain: expression and phosphorylation by endogenous protein kinases

Suen, Piin-chau; Wu, Kuang‐Chong; Jia-ling, XU; Lin, Siang-Yo; Levine, Eric S.; Black, Ira B.

doi:10.1016/s0169-328x(98)00157-0

Cited by 88 publications

(62 citation statements)

References 37 publications

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“…Furthermore, lOR stimulation triggers the activation of NMDA receptors by increasing intracellular PKC activity (Chen and Huang, 1991) as well as translocation of the cytosolic PKCc to the plasma membrane leading to phosphorylation of the NMDA receptors implicated in pain promotion (Suen et al, 1998). Evidence for NMDA receptor activation during the hyperalgesic response to low dose morphine administration was recently demonstrated (Holtman and Wala, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…This effect was dose dependent. PKCc associates physically with NMDA NR1 subunit in the postsynaptic density in rat brain, suggesting that these receptors may be directly phosphorylated by the kinase, leading to enhancement of synaptic activity (Suen et al, 1998). The majority of NMDA NR1 labeled dendrites contained lOR labeling in ventrolateral PAG (Commons et al, 1999), a supraspinal brainstem region of interest because of its established role in modulation of nociceptive transmission.…”

Section: Discussionmentioning

confidence: 99%

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Signaling pathway of morphine induced acute thermal hyperalgesia in mice

Galeotti

Stefano

Guarna

et al. 2006

Pain

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Systemic administration of morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 lg/kg). We have examined in vivo whether morphine, at an extremely low dose, induces acute central hypernociception following activation of the opioid receptor-mediated PLC/PKC inositol-lipid signaling pathway. The PLC inhibitor U73122 and the PKC blocker, calphostin C, dose dependently prevented the thermal hypernociception induced by morphine. This effect was also prevented by pretreatment with aODN against PLCb 3 at 2 nmol/mouse and PKCc at 2-3 nmol/mouse. Low dose morphine hyperalgesia was dose dependently reversed by selective NMDA antagonist MK801 and ketamine. This study demonstrates the presence of a nociceptive PLCb 3 /PKCc/NMDA pathway stimulated by low concentrations of morphine, through lOR 1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in morphine analgesia. When mice were treated with a morphine analgesic dose (7 mg/kg), the downregulation of PLCb 3 or PKCc at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in analgesic response. Experimental and clinical studies suggest that opioid may activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. The clinical management of pain by morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway. Ó

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Signaling pathway of morphine induced acute thermal hyperalgesia in mice

Galeotti

Stefano

Guarna

et al. 2006

Pain

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“…Furthermore, in hippocampal neurons, trkB receptor activation leads to phosphorylation of NMDA receptor subunits I and 2B (26,38) and increases the open probability of these channels (39,40). We compared the size of the NMDA receptor-dependent component of the VRP in BDNF ϩ/ϩ and BDNF Ϫ/Ϫ animals.…”

Section: Discussionmentioning

confidence: 99%

BDNF but not NT-4 is required for normal flexion reflex plasticity and function

Heppenstall

Lewin²

2001

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

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Neurotrophins can directly modulate the function of diverse types of central nervous system synapses. Brain-derived neurotrophic factor (BDNF) might be released by nociceptors onto spinal neurons and mediate central sensitization associated with chronic pain. We have studied the role of BDNF and neurotrophin-4 (NT-4), both ligands of the trkB tyrosine kinase receptor, in synaptic transmission and reflex plasticity in the mouse spinal cord. We used an in vitro spinal cord preparation to measure monosynaptic and polysynaptic reflexes evoked by primary afferents in BDNF-and NT-4-deficient mice. In situ hybridization studies show that both these neurotrophins are synthesized by sensory neurons, and NT-4, but not BDNF, also is expressed by spinal neurons. BDNF null mutants display selective deficits in the ventral root potential (VRP) evoked by stimulating nociceptive primary afferents whereas the non-nociceptive portion of the VRP remained unaltered. In addition, activity-dependent plasticity of the VRP evoked by repetitive (1 Hz) stimulation of nociceptive primary afferents (termed windup) was substantially reduced in BDNF-deficient mice. This plasticity also was reduced in a reversible manner by the protein kinase inhibitor K252a. Although the trkB ligand NT-4 is normally present, reflex properties in NT-4 null mutant mice were normal. Pharmacological studies also indicated that spinal N-methyl-D-aspartate receptor function was unaltered in BDNF-deficient mice. Using immunocytochemistry for markers of nociceptive neurons we found no evidence that their number or connectivity was substantially altered in BDNF-deficient mice. Our data therefore are consistent with a direct role for presynaptic BDNF release from sensory neurons in the modulation of pain-related neurotransmission.B rain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are structurally related neurotrophins that act through a common tyrosine kinase trkB receptor and regulate neuronal survival and differentiation (1). In addition, it is now known that neurotrophins are powerful modulators of both peripheral and central nervous system synapses (2). Thus both basal synaptic transmission and long-term synaptic plasticity can be regulated by neurotrophins (3).In the spinal cord, a form of synaptic plasticity termed central sensitization underlies many forms of hyperalgesia, and neurotrophins play an important role in this process (4, 5). For example, the hyperalgesia and pain associated with peripheral inflammation depends on up-regulation of nerve growth factor (NGF) in inflamed tissues (6-8). NGF can directly sensitize primary afferent nociceptors expressing the trkA receptor and also indirectly increase primary afferent connectivity in the spinal cord (6, 9, 10, 11). BDNF is synthesized by trkA-positive sensory neurons, and NGF treatment dramatically increases levels of BDNF in these neurons (12). Furthermore, BDNF is anterogradely transported to the spinal terminals of nociceptive neurons where it is localized in dense core vesicles and pres...

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“…Immunoprecipitation and Western Blotting-PSD proteins were solubilized at 4°C for 2 h in a low stringent buffer (16) or at 4°C for 30 min in 50 mM Tris-HCl buffer (pH 7.5) containing 137 mM NaCl, 2.7 mM KCl, 5 mM EDTA, 5 mM EGTA, 2% SDS, 50 mM NaF, 100 M sodium vanadate, and protease inhibitor mixture (solubilization buffer). In the latter case, five volumes of dilution buffer containing 2% Triton X-100 (17) were further added and incubated at 4°C for an additional 2 h. The supernatant was obtained after centrifugation at 10,000 rpm for 10 min, incubated at 4°C for 3 h or overnight with antibodies, and then mixed for 2 h with protein G plus/protein A-agarose.…”

Section: Methodsmentioning

confidence: 99%

Characterization of a Novel synGAP Isoform, synGAP-β

Li¹,

Okano²,

Tian³

et al. 2001

Journal of Biological Chemistry

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We cloned a cDNA encoding a novel synGAP, syn-GAP-d (GenBank TM accession number AB016962), from a rat brain cDNA library. The clone consisted of 4801 nucleotides with a coding sequence of 3501 nucleotides, encoded a protein consisting of 1166 amino acids with >99% homology with 1092 amino acid overlaps to syn-GAP, and contained a 13-nucleotide insertion to the previously reported synGAP mRNAs, which suggested that the clone was a splice variant of synGAP. We also found that there are at least seven variants in the 3 portion of the synGAP mRNA and that they encoded five different protein isoforms. The coding sequence of these C-terminal variants were classified into ␣1, ␣2, ␤1, ␤2, ␤3, ␤4, and ␥, and synGAP-d was classified as the ␤1 form. The previously reported synGAPs (synGAP-a, -b, and -c and p135synGAP) can be classified as the ␣1 isoform. All isoforms were expressed specifically in the brain. Unexpectedly, the ␤ isoform, which lacks a C-terminal PSD-95-binding motif ((S/T)XV), was more restricted to the postsynaptic density fraction than the motif-containing ␣1 isoform. The ␤ isoform did not interact with PSD-95 but specifically interacted with a nonphosphorylated ␣ subunit of Ca 2؉

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NMDA receptor subunits in the postsynaptic density of rat brain: expression and phosphorylation by endogenous protein kinases

Cited by 88 publications

References 37 publications

Signaling pathway of morphine induced acute thermal hyperalgesia in mice

Signaling pathway of morphine induced acute thermal hyperalgesia in mice

BDNF but not NT-4 is required for normal flexion reflex plasticity and function

Characterization of a Novel synGAP Isoform, synGAP-β

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