Takeshi Suzuki

Keio University, Edo, Tōkyō, Japan

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Publications (51)85.35 Total impact

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    ABSTRACT: Adenosine deaminase acting on RNA 2 (ADAR2) catalyzes RNA editing at the glutamine/arginine (Q/R) site of GluA2, and an ADAR2 deficiency may play a role in the death of motor neurons in ALS patients. The expression level of ADAR2 mRNA is a determinant of the editing activity at the GluA2 Q/R site in human brain but not in cultured cells. Therefore, we investigated the extent of Q/R site-editing in the GluA2 mRNA and pre-mRNA as well as the ADAR2 mRNA and GluA2 mRNA and pre-mRNA levels in various cultured cell lines. The extent of the GluA2 mRNA editing was 100% except in SH-SY5Y cells, which have a much lower level of ADAR2 than the other cell lines examined. The ADAR2 activity at the GluA2 pre-mRNA Q/R site correlated with the ADAR2 mRNA level relative to the GluA2 pre-mRNA. SH-SY5Y cells expressed higher level of the GluA2 mRNA in the cytoplasm compared with other cell lines. These results suggest that the ADAR2 expression level reflects editing activity at the GluA2 Q/R site and that although the edited GluA2 pre-mRNA is readily spliced, the unedited GluA2 pre-mRNA is also spliced and transported to the cytoplasm when ADAR2 expression is low.
    No preview · Article · Feb 2012 · Neuroscience Research

  • No preview · Article · Dec 2010 · Neuroscience Research
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    ABSTRACT: GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.
    Full-text · Article · Sep 2010 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    Yuji Ikegaya · Takeshi Suzuki

    Preview · Article · May 2010 · Journal of Pharmacological Sciences
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    ABSTRACT: The motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS) express abundant Q/R site-unedited GluR2 mRNA, whereas those of patients with other motor neuron diseases including familial ALS associated with mutated SOD1 (ALS1) and those of normal subjects express only Q/R site-edited GluR2 mRNA. Because adenosine deaminase acting on RNA type 2 (ADAR2) specifically catalyzes GluR2 Q/R site-editing, it is likely that ADAR2 activity is not sufficient to edit this site completely in motor neurons of patients with sporadic ALS. Because these molecular abnormalities occur in disease- and motor neuron-specific fashion and induce fatal epilepsy in mice, we have hypothesized that GluR2 Q/R site-underediting due to ADAR2 underactivity is a cause of neuronal death in sporadic ALS. We found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position using RNA interference knockdown. Our review will include a discussion of new ADAR2 substrates that may be useful for research on sporadic ALS.
    No preview · Article · May 2010 · Journal of Pharmacological Sciences

  • No preview · Article · Dec 2007 · Neuroscience Research
  • Article: P3-350
    Takeshi Suzuki · James R. Brorson · Kwak Shin

    No preview · Article · Jul 2006
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    ABSTRACT: For pathophysiological studies, it is advantageous to label specific neuronal populations in living animals. This study aimed to establish a method for stable and long-lasting fluorescent labeling of corticospinal neurons in the living animal. The two fluorescent dyes Fluoro-Red and Fluoro-Green were injected in the cervical spinal cord of anesthetized newborn rats. After a recovery period, treated rats were returned to the mother. After 24 h and 14 days, fixed brain sections revealed wide-spread fluorescence in elongated or pyramidal-shaped cell profiles in a discrete internal cortical layer, consistent with layer V pyramidal cells. Labeled neurons displayed spontaneous synaptic activity using the slice patch clamp method. These results suggest that these dyes are effective tools for pathophysiological and slice patch clamp studies focused on specific neuron groups.
    Preview · Article · Sep 2004 · Brain Research Protocols
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    James R Brorson · Dongdong Li · Takeshi Suzuki
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    ABSTRACT: Initial models of AMPA receptor assembly postulated the unrestricted stochastic association of individual subunits. The low Ca(2+) permeability and nonrectified current-voltage relationship of most native AMPA receptors were ascribed to dominant effects of the glutamate receptor 2 (GluR2) subunit. A recent model, however, proposes instead the preferred assembly of GluR1 and GluR2 subunits into tetrameric complexes as pairs of identical heteromeric dimers. To compare unrestricted versus selective models of GluR1 and GluR2 assembly, these subunits, in both flip and flop isoforms, were expressed in varying ratios in human embryonic kidney 293 cells. Coexpression of pairs of wild-type subunits produced expression of a predominance of heteromeric over homomeric receptors. Only a single functional type of heteromeric receptor was observed, indicating a pattern of apparent dominance not only of GluR2 for ion selectivity, but also of the flip isoform for receptor desensitization. Expression of wild-type GluR1 flip, however, with a mutant form of the same subunit carrying an arginine residue at the glutamine/arginine site (GluR1(R) flip) demonstrated a lack of dominance of GluR1(R) in determination of ion selectivity, whereas expression of GluR1(R) flip with GluR1 flop reproduced the pattern of apparent complete dominance. Together, the data support the selective expression of heteromeric receptors and are compatible with an equilibrium model of assembly of tetramers as pairs of identical heteromeric dimers. Expression of co-assemblies of the flip and flop isoforms, like that of the GluR1 and GluR2 subunits, is strongly favored over that of homomeric assemblies.
    Preview · Article · May 2004 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
  • Takeshi Suzuki · Ryoichi Takagi · Koichiro Kawashima
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    ABSTRACT: GABA is a major inhibitory neurotransmitter in the mature mammalian brain. In the early stages of brain development, it has been reported that GABA(A) receptor stimulation and the associated increase in Cl(-) conductance lead to membrane depolarization. In this study, we tested the effects of picrotoxin, a GABA(A) receptor Cl(-) channel blocker, on spontaneously released acetylcholine (ACh) from cultured rat embryonic septal cells. Picrotoxin increased spontaneously released ACh. These results indicate that blockade of GABA-activated Cl(-) channel increases neuronal excitability even in an early stage of the development.
    No preview · Article · Mar 2004 · Neuroscience Letters
  • Takeshi Suzuki · Keisuke Tsuzuki · Kimihiko Kameyama · Shin Kwak
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    ABSTRACT: As glutamate is a dominant excitatory neurotransmitter in the central nervous system, glutamate receptors, and especially AMPA receptors, are located ubiquitously in all brain areas. In this paper, we reviewed recent advances of studies on AMPA receptor functions. AMPA receptors are cation-conducting complexes composed of various combinations of four subunits (GluR1 to GluR4). The glutamine residue located in the pore-forming segment of GluR2 subunit (Q/R site) is changed to arginine by RNA editing at the pre mRNA stage in normal adult mammalian animal. The edited GluR2 subunit is a major determination of Ca(2+) permeability of the AMPA receptor; only edited GluR2-lacking receptor shows high-Ca(2+) permeability. The assembly of glutamate AMPA receptor subunit is not completely according to the stochastic theory. The heteromeric subunits assembly is more rapid than the homomeric assembly is. The transfer of AMPA receptor subunit to the plasma membrane is conducted in multiple ways. Many molecules that interact with the intracellular domain of AMPA receptor subunits are reported as the modulators of AMPA receptor subunit transfer. In the motoneuron of sporadic amyotrophic lateral sclerosis (ALS) patients, the efficiency of RNA editing at the GluR2 Q/R site is significantly decreased. Relative low level of edited GluR2 subunit expression is likely responsible for motoneuronal death in ALS. Recently, AMPA receptors in glial cells have been studied. Bergmann glial cells in cerebellum express Ca(2+)-permeable AMPA receptors. Conversion of these AMPA receptors to Ca(2+)-impermeable type receptors induces morphological and functional changes. Glioblastoma cells also express Ca(2+)-permeable AMPA receptors, and their conversion to Ca(2+)-impermeable receptors inhibits cell locomotion and induces apoptosis.
    No preview · Article · Jan 2004 · Folia Pharmacologica Japonica
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    ABSTRACT: We tested the characteristics of acetylcholine (ACh) release from cultured rat septal cells. The spontaneous release was inhibited by treatment with tetrodotoxin (TTX) and omega-conotoxin (GVIA), indicating that the release was elicited by synaptic activity. The release was also inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor blocker, in both the absence and presence of nerve growth factor (NGF), suggesting that endogenously released glutamate produced the ACh release by stimulating AMPA receptors. This is the first report of detection of the release of ACh by endogenous spontaneous synaptic activity conducted by glutamate AMPA receptor activation in cultured septal cells. This in vitro experimental system is useful for the study of cholinergic functions.
    No preview · Article · Nov 2003 · Neuroscience Research
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    ABSTRACT: We examined the development of cholinergic neuronal functions and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) responses in cultured embryonic rat septal cells. Choline acetyltransferase activity was increased from 4 to 6 days in culture and reached a plateau at day 8. Acetylcholine release was increased from 6 to 8 days in culture. AMPA-induced increase in intracellular Ca(2+) level was observed at 3 days in culture and most of the AMPA-responsive cells coincided with high-K(+) responsive cells. These results suggest that cholinergic neurons develop their neuronal functions about 8 days under cultured conditions, and functional expression of AMPA receptors precedes the cholinergic functional development.
    No preview · Article · Oct 2001 · Neuroscience Letters
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    ABSTRACT: A possible involvement of serotonin-mediated cholinergic activation in the antidepressant effect of desmethylimipramine (DMI) was investigated by determination of the effects of a single or repeated DMI administration on acetylcholine (ACh) release in the hippocampus using an in vivo microdialysis technique and a radioimmunoassay for ACh. Rats were administered DMI (10 mg/kg, i.p.) acutely or repeatedly for 21 days. A single or repeated DMI administration did not cause any significant effects on the basal ACh release compared with the respective controls. Atropine perfusion in the acutely DMI-treated or control rats increased the ACh release to the same degree. In repeatedly DMI-treated rats, serotonin (5-HT) (1 to 10 microM) perfusion enhanced significantly the ACh release. However, 5-HT in acutely DMI-treated rats enhanced significantly the ACh release only at 10 microM. 5-HT did not cause any changes in ACh release in control rats. Hippocampal 5-HT content of acutely DMI-treated rats was significantly higher than that of saline-treated control rats, while no difference was observed between the repeatedly DMI- and saline-treated rats. These findings suggest, for the first time, that DMI induced a facilitation of cholinergic neurotransmission in the rat hippocampus through the activation of 5-HT-receptor function.
    Full-text · Article · Sep 1999 · The Japanese Journal of Pharmacology
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    ABSTRACT: The mechanisms involved in the enhancement of acetylcholine (ACh) release in the rat hippocampus by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a serotonin (5-HT)1A receptor agonist, were investigated using in vivo microdialysis. Administration of p-chlorophenylalanine (PCPA, 300 mg/kg, i.p.), a tryptophan hydroxylase inhibitor, 3 days before the dialysis experiments reduced the hippocampal 5-HT content to 30% of that in saline-treated rats, but did not affect basal ACh release in the hippocampus. 8-OH-DPAT administered systemically (0.5 mg/kg, s.c.) or applied locally (30 μM) into the hippocampus through the dialysis probe significantly enhanced the release of ACh in the hippocampus of PCPA-treated rats to the same degree as that in saline-treated rats. Pretreatment with (+)WAY-100135 (5 mg/kg, i.p.), a selective 5-HT1A receptor antagonist, completely eliminated the enhancement of ACh release induced by locally applied 8-OH-DPAT, but only partially reduced the effects induced by systemically administered 8-OH-DPAT, in both groups of rats. Systemically administered 8-OH-DPAT induced hyperlocomotion in the both saline- and PCPA-treated rats, but this was not eliminated by (+)WAY-100135. 8-OH-DPAT applied locally into the hippocampus did not elicit hyperlocomotion in either group of rats. These results suggest that the modification of endogenous 5-HT release via the 5-HT1A autoreceptor is not involved in the 8-OH-DPAT-induced increase of hippocampal ACh release, and that the increase of ACh release induced by locally applied 8-OH-DPAT involves mainly hippocampal postsynaptic 5-HT1A receptor stimulation. In addition, a possibility that subtypes of 5-HT receptors other than the 5-HT1A receptor, probably 5-HT7 receptor in the septum as well as postsynaptic 5-HT1A receptor in the hippocampus, are involved in the increased hippocampal ACh release induced by systemically administered 8-OH-DPAT is discussed.
    No preview · Article · Jun 1998 · Neuroscience Research

  • No preview · Article · Dec 1997 · Neuroscience Research

  • No preview · Article · Dec 1997 · Neuroscience Research
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    ABSTRACT: The role of the serotonin (5-HT)1A receptor in the regulation of acetylcholine (ACh) release in the hippocampus was investigated using an in vivo microdialysis technique and a sensitive radioimmunoassay specific for ACh. The mean (+/- S.E.M.) basal ACh contents in the hippocampal perfusate of conscious, freely moving rats was 60 +/- 4 (n = 29) and 3691 +/- 265 fmol/30 min (n = 31), respectively, in the absence and presence of physostigmine (Phy) in the perfusion fluid. Systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.5 mg/kg, s.c.), a 5-HT1A agonist, significantly enhanced ACh release both in the presence and absence of Phy. Local application of 8-OH-DPAT (3-30 microM) into the hippocampus through the microdialysis probe significantly potentiated ACh release only in the presence of Phy, whereas no significant effect was observed in its absence. Pretreatment with NAN-190 (3 mg/kg, i.p.), a 5-HT1A antagonist, eliminated the increasing effect of systemically applied 8-OH-DPAT on ACh release, while NAN-190 alone had no effect on basal ACh release either in the absence or presence of Phy. Consistent with the time course of ACh release, systemic administration of 8-OH-DPAT evoked hyperlocomotion, which was reversed by NAN-190. However, local hippocampal application of 8-OH-DPAT did not affect the locomotor activity of the rats. These findings suggest that at least two different sites are involved in the 8-OH-DPAT-induced increase in the release of ACh in the rat hippocampus in vivo.
    No preview · Article · Aug 1997 · Brain Research
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    ABSTRACT: Nitric oxide (NO) is an endothelium-derived relaxing factor and its main mechanism of action is activation of soluble guanylyl cyclase. NO and NO-related compounds have been reported to affect several neuronal functions in the central nervous system. In this study, we investigated the effects of NO donors (sodium nitroprusside (SNP) and (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409)) on acetylcholine (ACh) release from rat hippocampal slices. SNP (10(-5) M) and FK409 (10(-4) M) increased electrical stimulation-evoked ACh release without affecting basal release. As dibutyryl cyclic GMP inhibited stimulation-evoked ACh release, the effects of these NO donors were not due to soluble guanylyl cyclase activation. Atropine increased stimulation-evoked ACh release by blocking presynaptic muscarinic autoreceptors, and SNP increased stimulation-evoked ACh release in the presence of atropine, suggesting that SNP and atropine increase stimulation-evoked ACh release by different mechanisms. The present results indicate that NO enhances some part of the excitation-secretion coupling pathway without inducing ACh release directly and these effects are mediated by cyclic GMP-independent mechanism.
    No preview · Article · Jul 1997 · Brain Research
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    ABSTRACT: YM358 (2,7-diethyl-5-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]-triazole potassium salt), a novel nonpeptide angiotensin AT(1)-receptor antagonist, was administered daily for 4 weeks to 24-week-old stroke-prone spontaneously hypertensive rats (SHRSP). Its effects on systolic, mean and diastolic arterial pressure (SAP, MAP and DAP), heart rate and locomotor activity were investigated by using radiotelemetry. A clear diurnal Variation in blood pressure, heart rate and locomotor activity was observed in synchrony with the light cycle. YM358 at a daily oral dose of 10 or 30 mg/kg produced a reduction of blood pressure in a dose-dependent manner. Although a mild attenuation of the antihypertensive effect of YM358 was observed during the early stage of therapy, YM358 at 30 mg/kg per day produced a significant and consistent decrease in 24-hr MAP and DAP, and it prevented the further development of hypertension. YM358 did not affect either heart rate or locomotor activity or their diurnal variations. After the discontinuation of therapy with YM358, the blood pressure recovered promptly to the control level while there was no sign of a rebound increase in blood pressure. These results suggest that YM358 may be potentially useful for the treatment of hypertension.
    No preview · Article · Jan 1997 · The Japanese Journal of Pharmacology

Publication Stats

769 Citations
85.35 Total Impact Points


  • 2010-2012
    • Keio University
      • Faculty of Pharmacy
      Edo, Tōkyō, Japan
  • 1987-2007
    • Kyoritsu College of Pharmacy
      • Department of Pharmacology
      Edo, Tōkyō, Japan
  • 2006
    • VA Puget Sound Health Care System
      Washington, Washington, D.C., United States
  • 2004
    • University of Chicago
      • Department of Neurology
      Chicago, Illinois, United States
  • 1995
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan