Publications (7)82.95 Total impact
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Article: IPP5 inhibits neurite growth in primary sensory neurons by maintaining TGF-β/Smad signaling.
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ABSTRACT: During nerve regeneration, neurite growth is regulated by both intrinsic molecules and extracellular factors. Here, we found that inhibitor 5 of protein phosphatase 1 (IPP5), a newly identified inhibitory subunit of protein phosphatase 1 (PP1), inhibited neurite growth in primary sensory neurons as an intrinsic regulator. IPP5 was highly expressed in rat primary sensory neurons localized in the dorsal root ganglion (DRG) and was downregulated after sciatic nerve axotomy. Knocking down IPP5 with specific shRNA increased the length of the longest neurite, the total neurite length and the number of neurite ends in cultured rat DRG neurons. Mutation of the PP1 binding motif "(8)KIQF(12)" or the PP1 inhibiting motif at Thr(34) eliminated the IPP5-induced inhibition of neurite growth. Furthermore, biochemical experiments showed that IPP5 interacted with type I transforming growth factor-β receptor (TβRI) and PP1 and enhanced transforming growth factor-β (TGF-β)/Smad signaling in a PP1-dependent manner. Overexpressing IPP5 in DRG neurons aggravated TGF-β-induced inhibition of neurite growth, which was abolished by blocking PP1 or IPP5 binding to PP1. Blockage of TGF-β signaling with TβRI inhibitor SB431542 or Smad2 shRNA attenuated the IPP5-induced inhibition of neurite growth. Thus, these data indicate that selectively expressed IPP5 inhibits neurite growth by maintaining TGF-β signaling in primary sensory neurons.Journal of Cell Science 11/2012; · 6.11 Impact Factor -
Article: Oral sildenafil treatment for Eisenmenger syndrome: a prospective, open-label, multicentre study.
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ABSTRACT: Although sildenafil has been shown to be safe and effective in idiopathic pulmonary arterial hypertension (PAH) and PAH related to connective tissue disease, its effects in Eisenmenger syndrome are less clear. To investigate whether long-term treatment (12 months) with the phosphodiesterase type 5 inhibitor sildenafil improves clinical and haemodynamic parameters in patients with Eisenmenger syndrome. Prospective, open-label, multicentre study. Four pulmonary hypertension centres in China. 84 Eisenmenger syndrome functional class II-IV patients. Oral sildenafil 20 mg orally three times a day. 6-min walk distance (6MWD) test, resting systemic arterial blood oxygen saturation (SaO(2)) in room air, haemodynamic parameters assessed by right heart catheterisation, safety and tolerability. The overall treatment effects at 12 months versus baseline (mean changes with 95% CIs) were 56 m increase (42 to 69, p<0.0001) in 6MWD, and 2.4% increase (1.8% to 2.9%, p<0.0001) in resting room air SaO(2). Improvements were also seen in mean pulmonary arterial pressure and pulmonary vascular resistance index (-4.7 mm Hg (-7.5 to -1.9), p=0.001; and -474 dyn×s×cm(-5)×m(2) (-634 to -314), p<0.0001, respectively). Sildenafil was well tolerated. Most adverse events were mild and transient, and occurred in the first 2 weeks of treatment. Twelve months of oral sildenafil treatment was well tolerated and appeared to improve exercise capacity, systemic arterial oxygen saturation and haemodynamic parameters in patients with Eisenmenger syndrome.Heart (British Cardiac Society) 09/2011; 97(22):1876-81. · 4.22 Impact Factor -
Article: Facilitation of μ-opioid receptor activity by preventing δ-opioid receptor-mediated codegradation.
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ABSTRACT: δ-opioid receptors (DORs) form heteromers with μ-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradation. Treatment with DOR-specific agonists led to endocytosis of both DORs and MORs. These receptors were further processed for ubiquitination and lysosomal degradation, resulting in a reduction of surface MORs. Such effects were attenuated by treatment with an interfering peptide containing the first transmembrane domain of MOR (MOR(TM1)), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MOR(TM1) and TAT at the C terminus could disrupt the MOR/DOR interaction in the mouse spinal cord, enhance the morphine analgesia, and reduce the antinociceptive tolerance to morphine. Thus, dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies.Neuron 01/2011; 69(1):120-31. · 14.74 Impact Factor -
Article: Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons.
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ABSTRACT: Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between delta-opioid receptors (DORs) and mu-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca(2+) currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.Proceedings of the National Academy of Sciences 07/2010; 107(29):13117-22. · 9.68 Impact Factor -
Article: Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons
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ABSTRACT: Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between δ-opioid receptors (DORs) and μ-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca2+ currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.Proceedings of the National Academy of Sciences 07/2010; 107(29):13117-13122. · 9.68 Impact Factor -
Article: The voltage-gated Na+ channel Nav1.8 contains an ER-retention/retrieval signal antagonized by the beta3 subunit.
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ABSTRACT: Voltage-gated Na(+) channel (Na(v)) 1.8 contributes to the majority of the Na(+) current that underlies the depolarizing phase of action potentials. Na(v)1.8 is mainly distributed intracellularly and its current amplitude can be enhanced by the beta3 subunit. However, little is known about the mechanisms underlying its intracellular retention and the effects mediated by the beta3 subunit. Here, we show that the beta3 subunit promotes surface expression of Na(v)1.8 by masking its endoplasmic reticulum (ER)-retention/retrieval signal. The RRR motif in the first intracellular loop of Na(v)1.8 is responsible for retaining Na(v)1.8 in the ER and restricting its surface expression. The beta3 subunit facilitates surface expression of Na(v)1.8. The intracellular C-terminus of the beta3 subunit interacts with the first intracellular loop of Na(v)1.8 and masks the ER-retention/retrieval signal. Mutation of the RRR motif results in a significant increase in surface expression of Na(v)1.8 and abolishes the beta3-subunit-mediated effects. Thus, the beta3 subunit regulates surface expression of Na(v)1.8 by antagonizing its ER-retention/retrieval signal. These results reveal a novel mechanism for the effect of the Na(+) channel beta subunits on the alpha subunits.Journal of Cell Science 10/2008; 121(Pt 19):3243-52. · 6.11 Impact Factor -
Article: Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia.
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ABSTRACT: Opioid and tachykinin systems are involved in modulation of pain transmission in the spinal cord. Regulation of surface opioid receptors on nociceptive afferents is critical for opioid analgesia. Plasma-membrane insertion of delta-opioid receptors (DORs) is induced by stimulus-triggered exocytosis of DOR-containing large dense-core vesicles (LDCVs), but how DORs become sorted into the regulated secretory pathway is unknown. Here we report that direct interaction between protachykinin and DOR is responsible for sorting of DORs into LDCVs, allowing stimulus-induced surface insertion of DORs and DOR-mediated spinal analgesia. This interaction is mediated by the substance P domain of protachykinin and the third luminal domain of DOR. Furthermore, deletion of the preprotachykinin A gene reduced stimulus-induced surface insertion of DORs and abolished DOR-mediated spinal analgesia and morphine tolerance. Thus, protachykinin is essential for modulation of the sensitivity of nociceptive afferents to opioids, and the opioid and tachykinin systems are directly linked by protachykinin/DOR interaction.Cell 09/2005; 122(4):619-31. · 32.40 Impact Factor
Top co-authors
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Institutions
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2011
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Tongji Medical University
Shanghai, Shanghai Shi, China
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2005–2011
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Chinese Academy of Sciences
- • Molecular Biology & Cell Biology Laboratory
- • Institute of Neuroscience (SIBS)
Beijing, Beijing Shi, China
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2010
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Institute of Molecular Biology and Biochemistry
Graz, Styria, Austria
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