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Mitsuhiko Yamada

Publications and source records attributed to Mitsuhiko Yamada.

At least 37 records · Page 2Linked to original sources
PubMed2005

Phosphatidylinositol 3,4,5-trisphosphate and Ca2+/calmodulin competitively bind to the regulators of G-protein-signalling (RGS) domain of RGS4 and reciprocally regulate its action.

RGS (regulators of G-protein signalling) are a diverse group of proteins, which accelerate intrinsic GTP hydrolysis on heterotrimeric G-protein a subunits. They are involved in the control of a physiological behaviour known as 'relaxation' of G-protein-gated K+ channels in cardiac myocytes. The GTPase-accelerating activity of cardiac RGS proteins, such as RGS4, is inhibited by PtdIns(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate) and this inhibition is cancelled by Ca2+/calmodulin (CaM) formed during membrane depolarization. G-protein-gated K+ channel activity decreases on depolarization owing to the facilitation of GTPase-activating protein activity by RGS proteins and vice versa on hyperpolarization. The molecular mechanism responsible for this reciprocal control of RGS action by PtdIns(3,4,5)P3 and Ca2+/CaM, however, has not been fully elucidated. Using lipid-protein co-sedimentation assay and surface plasmon resonance measurements, we show in the present study that the control of the GTPase-accelerating activity of the RGS4 protein is achieved through the competitive binding of PtdIns(3,4,5)P3 and Ca2+/CaM within its RGS domain. Competitive binding occurs exclusively within the RGS domain and involves a cluster of positively charged residues located on the surface opposite to the Ga interaction site. In the RGS proteins conserving these residues, the reciprocal regulation by PtdIns(3,4,5)P3 and Ca2+/CaM may be important for their physiological regulation of G-protein signalling.

Acetylcholine↗
PubMed2005

Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy.

Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Pharmacogenomics is a powerful tool that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using this tool, others and we have identified as candidate molecular targets several genes or expressed sequence tags (ESTs) that are induced by chronic antidepressant treatment. In this article, we review antidepressant-elicited changes in gene expression, focusing especially on the remodeling of neuronal circuits that results. This refocusing motivates our hypothesis that this plasticity represents the mechanism for drug efficacy, and thus a causal event for clinical improvement. Defining the roles of these molecules in drug-induced neural plasticity is likely to transform the course of research on the biological basis of antidepressants. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. Consideration of novel biological approaches beyond the "monoamine hypothesis" of depression is expected to evoke paradigm shifts in the future of antidepressant research.

Animals↗
PubMed2005

Functional polymorphism of the NQO2 gene is associated with methamphetamine psychosis.

Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant (p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.

Adult↗
PubMed2004

A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.

Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia.

Adult↗
PubMed2004

Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes.

The inwardly rectifying K+ channel subunit Kir5.1 is expressed abundantly in the brain, but its precise distribution and function are still largely unknown. Because Kir5.1 is co-expressed with Kir4.1 in retinal glial Muller cells, we have compared the biochemical and immunological properties of Kir5.1 and Kir4.1 in the mouse brain. Immunoprecipitation experiments suggested that brain expressed at least two subsets of Kir channels, heteromeric Kir4.1/5.1 and homomeric Kir4.1. Immunolabeling using specific antibodies showed that channels comprising Kir4.1 and Kir5.1 subunits were assembled in a region-specific fashion. Heteromeric Kir4.1/5.1 was identified in the neocortex and in the glomeruli of the olfactory bulb. Homomeric Kir4.1 was confined to the hippocampus and the thalamus. Homomeric Kir5.1 was not identified. Kir4.1/5.1 and Kir4.1 expression appeared to occur only in astrocytes, specifically in the membrane domains facing the pia mater and blood vessels or in the processes surrounding synapses. Both Kir4.1/5.1 and Kir4.1 could be associated with PDZ domain-containing syntrophins, which might be involved in the subcellular targeting of these astrocyte Kir channels. Because heteromeric Kir4.1/5.1 and homomeric Kir4.1 have distinct ion channel properties (Tanemoto, M., Kittaka, N., Inanobe, A., and Kurachi, Y. (2000) J. Physiol. (Lond.) 525, 587-592 and Tucker, S. J., Imbrici, P., Salvatore, L., D'Adamo, M. C., and Pessia, M. (2000) J. Biol. Chem. 275, 16404-16407), it is plausible that these channels play differential physiological roles in the K+ -buffering action of brain astrocytes in a region-specific manner.

Animals↗
PubMed2004

Mutation in nucleotide-binding domains of sulfonylurea receptor 2 evokes Na-ATP-dependent activation of ATP-sensitive K+ channels: implication for dimerization of nucleotide-binding domains to induce channel opening.

The ATP-sensitive K+ (KATP) channel is composed of a sulfonylurea receptor (SUR) and a pore-forming subunit, Kir6.2. SUR is an ATP-binding cassette (ABC) protein with two nucleotide-binding domains (NBD1 and NBD2). Intracellular ATP inhibits KATP channels through Kir6.2 and activates them through NBDs. However, it is still unknown how ATP-bound NBDs activate KATP channels. A prokaryotic ABC protein, MJ0796, which is entirely NBD, forms a dimer in the presence of Na-ATP when its glutamate at position 171 is substituted with glutamine. Mg2+ or K+ destabilizes the dimer. We made the corresponding mutation in the NBD1 (D834N) and/or NBD2 (E1471Q) of SUR2A and SUR2B. As measured in the inside-out configuration of the patch-clamp method, SUR2x(D834N, E1471)/Kir6.2 channels mediated significantly larger currents in the presence of internal 1 mM Na-ATP than K-ATP alone or Mg-ATP. The response to Na-ATP resulted from an increase in the open probability but not single-channel amplitude of the channels and was abolished by glibenclamide (10(-5) M). In the presence of 1 mM Mg2+ -free ATP, Na+ increased the activity of the channels in a concentration-dependent manner. The Na-ATP-dependent activation was never observed with KATP channels including either the wild-type SUR2x, SUR2x(D834N), or SUR2x(E1471). Nicorandil activated SUR2x(D834N, E1471Q)/Kir6.2 channels more strongly in the presence of Na-ATP than K-ATP alone, whereas the reverse was true for wild-type SUR2x/Kir6.2 channels. Therefore, it is likely that NBDs of SUR2x dimerize in response to ATP and nicorandil. The dimerization induces the opening of the KATP channel, probably by causing a conformational change of SUR2x.

ATP-Binding Cassette Transporters↗
PubMed2004

Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.

Many drugs inhibit human ether-a-go-go related gene (HERG) current and prolong cardiac action potential duration. We examined the kinetic properties of quinidine block of HERG channels expressed in Xenopus oocytes in comparison with those of the block by a class III antiarrhythmic dofetilide. Both of the drugs inhibited HERG currents in a use-dependent and frequency-independent manner. However, the underlying mechanisms were different. Under the steady state, quinidine block was voltage- and time-dependent. At positive membrane potentials, the onset of block was very fast. Thus, quinidine caused frequency-independent block mainly through this fast blocking kinetic. In contrast, dofetilide blocked HERG currents in a voltage- and time-independent manner under the steady state because of very slow unblocking at negative potentials, which also caused frequency-independent block. Therefore, quinidine and dofetilide might cause the reverse frequency-dependent prolongation of action potential duration through distinct mechanisms with regard to blocking and unblocking kinetics.

Animals↗
PubMed2004

Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers.

Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non-deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects.

Adult↗
PubMed2004

Clinical pharmacology of MAO inhibitors: safety and future.

In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called "cheese effect." Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.

Alzheimer Disease↗
PubMed2004

The nucleotide-binding domains of sulfonylurea receptor 2A and 2B play different functional roles in nicorandil-induced activation of ATP-sensitive K+ channels.

Nicorandil activates ATP-sensitive K(+) channels composed of Kir6.2 and either sulfonylurea receptor (SUR) 2A or 2B. Although SUR2A and SUR2B differ only in their C-terminal 42 amino acids (C42) and possess identical drug receptors and nucleotide-binding domains (NBDs), nicorandil more potently activates SUR2B/Kir6.2 than SUR2A/Kir6.2 channels. Here, we analyzed the roles of NBDs in these channels' response to nicorandil with the inside-out configuration of the patch-clamp method. Binding and hydrolysis of nucleotides by NBDs were impaired by mutations in the Walker A motif of NBD1 (K708A) and NBD2 (K1349A) and in the Walker B motif of NBD2 (D1470N). Experiments were done with internal ATP (1 mM). In SUR2A/Kir6.2 channels, the K708A mutation abolished, and the K1349A but not D1470N mutation reduced the sensitivity to nicorandil. ADP (100 microM) significantly increased the wild-type channels' sensitivity to nicorandil, which was abolished by the K1349A or D1470N mutation. Thus, the SUR2A/Kir6.2 channels' response to nicorandil critically depends on ATP-NBD1 interaction and is facilitated by interactions of ATP or ADP with NBD2. In SUR2B/Kir6.2 channels, either the K708A or K1349A mutation partially suppressed the response to nicorandil, and double mutations abolished it. The D1470N mutation also significantly impaired the response. ADP did not sensitize the channels. Thus, NBD2 hydrolyzes ATP, and NBD1 and NBD2 equally contribute to the response by interacting with ATP and ADP, accounting for the higher nicorandil sensitivity of SUR2B/Kir6.2 than SUR2A/Kir6.2 channels in the presence of ATP alone. Thus, C42 modulates the interaction of both NBDs with intracellular nucleotides.

Adenosine Diphosphate↗
PubMed2004

Gene polymorphisms of the mu opioid receptor in methamphetamine abusers.

In drug addiction, the opioid system is thought to mediate motivational effects through dopamine-independent mechanisms. We have investigated associations of the mu-opioid receptor gene (OPRM) variations with methamphetamine (MAP) dependence/psychosis. The allelic frequency of A118G (Asn40Asp) in exon 1 of ORPM was 45.3% in our control subjects, but only 7.5-25.8% in the Caucasian or African-American population of previous studies. We have identified several novel polymorphisms in intron 1 and the 5' untranslated region (5'UTR) of OPRM. Polymorphisms in the functionally relevant 5' regulatory region of OPRM were different in our Japanese population from Caucasian or African-American populations. No significant differences between controls and MAP abusers were found in either genotype or allele frequency at any single nucleotide polymorphism (SNP) or (AC)n dinucleotide repeat in intron 1. A subdivision of our MAP group revealed that A118G of OPRM shows a significant association with MAP psychosis having latency less than three years. Further analysis should be capable of identifying associations between the OPRM variations and MAP dependence/psychosis.

Adult↗
PubMed2004

Study of association between alpha-synuclein gene polymorphism and methamphetamine psychosis/dependence.

Methamphetamine (MAP) dissipates proton gradients across the membranes of synaptic vesicles, enhances cytoplasmic dopamine (DA) concentrations, and causes calcium-independent, nonvesicular DA release into synapses. MAP is taken into the cytosol by the dopamine transporter (DAT) on the synaptic terminals of DA neurons, and endogenous DA is concurrently released through the transporter by carrier exchange mechanisms, resulting in a robust increase in DA concentration in the synaptic clefts. The enhanced DA release through DAT by MAP is the main mechanism for the reinforcing effects of MAP. The complexes of alpha-synuclein and DAT facilitate membrane clustering of the DAT, thereby accelerating DA uptake in vitro. alpha-Synuclein has been shown to be overexpressed in the midbrain DA neurons of chronic cocaine abusers. The present study was performed to study the association between the alpha-synuclein gene polymorphisms and MAP psychosis/dependence in Japanese population. Since the T10A7 polymorphic site at the 5' end of the noncoding exon 1' in the alpha-synuclein gene is highly polymorphic, we analyzed the noncoding exon 1' and intron 1, including this polymorphic site by sequencing. We confirmed four single nucleotide polymorphisms (SNPs) within 1.38 kbp of the T10A7 polymorphic site. No significant difference was found in genotype or allele frequencies in the T10A7 polymorphic site between MAP psychotic/dependent and control subjects. We found significant association between three SNPs in the vicinity of this polymorphic site in intron 1 and MAP psychosis/dependence in female subjects, but not in males. These results suggest an association of the alpha-synuclein gene polymorphisms with MAP psychosis/dependence in our female subjects. Further analyses are necessary to clarify the gender difference, by using a larger sample size and/or different ethnic groups, as well as functional variations in the alpha-synuclein gene.

Adult↗
PubMed2004

[Future antidepressant research and pharmacogenomics].

Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Using pharmacogenomics tools, we and other investigators have identified as candidate molecular targets several genes or expressed sequence tags (ESTs) that are induced by chronic antidepressant treatment. In this article, we review antidepressant-elicited changes in gene expression, focusing especially on the remodeling of neuronal circuits that results. This refocusing motivates our hypothesis that this plasticity represents the mechanism for drug efficacy, and thus a causal event for clinical improvement. Consideration of novel biological approaches beyond the "monoamine hypothesis" of depression is expected to evoke paradigm shifts in the future of antidepressant research.

Antidepressive Agents↗
PubMed2003

Scanning electron microscopy of food-poisoning bacterium Bacillus cereus using a variable-pressure SEM.

A variable-pressure scanning electron microscopy (VP-SEM) with a cooling stage permits long hours of observation of water-containing specimens in their natural or close to natural state, without the conventional specimen preparations of fixation, dehydration, drying and metal coating. It reduces water vaporization and beam damage by keeping the specimens at a low temperature. We observed Bacillus cereus colonies on nutrient agar, which would shrink significantly if any conventional specimen preparation technique were used. We also studied the growing process of the bacteria on raw and steamed rice using the VP-SEM without conventional preparation techniques. Original specimens were directly mounted onto specimen holders and their backscattered electron images observed under the following conditions: specimen stage temperature, -10 degrees C; specimen chamber vacuum level, 30-70 Pa; and accelerating voltage, 15-20 kV. We recognized that the VP-SEM minimized deformation of the colonies due to shrinkage of the nutrient agar, and successfully imaged the morphology of the colonies and bacteria without a decline in bacteria number, which is apt to occur during fixation and dehydration. Also, the growth process of the bacteria on raw or steamed rice could be observed promptly, since there is no specimen preparation step.

Animals↗
PubMed2003

Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels.

A novel antidiabetic agent, nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of nateglinide on recombinant ATP-sensitive K(+) (K(ATP)) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K(i) = 75 nM and 114 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide. MgADP or MgUDP (100 microM) augmented the inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of nateglinide (approximately 10 microM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.

ATP-Binding Cassette Transporters↗
PubMed2003

[Molecular and functional diversity of ATP-sensitive K+ channels: the pathophysiological roles and potential drug targets].

ATP-sensitive K(+) (K(ATP)) channels comprise the pore-forming subunit (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptors (SUR1 or SUR2). K(ATP) channels with different combinations of these subunits are present in various tissues and regulate cellular functions. From the analysis of mouse models with targeted deletion of the gene encoding the pore-forming subunit Kir6.1 or Kir6.2, functional roles of K(ATP) channels in various organs have been clarified. Kir6.1(-/-) mice showed sudden death associated with ST elevation and atrioventricular block in ECG, a phenotype resembling Prinzmetal angina in humans. Kir6.2(-/-) mice were more susceptible to generalized seizure during hypoxia than wild-type (WT) mice, suggesting that neuronal K(ATP) channels, probably composed of Kir6.2 and SUR1, play a crucial role for the protection of the brain against lethal damage due to seizure. In Kir6.2(-/-) mice lacking the sarcolemmal K(ATP) channel activity in cardiac cells, ischemic preconditioning failed to reduce the infarct size, suggesting that sarcolemmal K(ATP) channels play an important role in cardioprotection against ischemia/reperfusion injuries in the heart. Mitochondrial K(ATP) channels have been also proposed to play a crucial role in cardioprotection, although the molecular identity of the channel has not been established. Nicorandil and minoxidil, K(+) channel openers activating mitochondrial K(ATP) channels, decreased the mitochondrial membrane potential, thereby preventing the Ca(2+) overload in the mitochondria of guinea-pig ventricular cells. SURs are the receptors for K(+) channel openers and the activating effects on sarcolemmal K(ATP) channels in cardiovascular tissues could be modulated by the interaction of nucleotides. Due to the molecular diversity of the accessory and pore subunits of K(ATP) channels, there would be considerable differences in the tissue selectivity of K(ATP) channel-acting drugs. Studies of Kir6.1 and Kir6.2 knockout mice indicate that K(ATP) channels are involved in the mechanisms of the protection against metabolic stress. Further clarification of physiological as well as pathophysiological roles of K(ATP) channels may lead to a new therapeutic strategy to improve the quality of life.

ATP-Binding Cassette Transporters↗