Exploratory Research Center on Life and Living Systems     National Institute for Physiological Sciences

Division of Cardiocirculatory Signaling

 【Invited Seminars】
 Date: 2019/3/27 PM3:00~4:00
Speaker:Hyoung Kyu Kim,Associate professor (Cardiovascular and Metabolic Disease Center (CMDC). Inje University)
Title: A novel role of tetrahydrobiopterin in cardiovascular system
Diabetic cardiomyopathy (DCM) is a major cause of mortality and morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous target in the cardiovascular system, its effect on myocardial cells and mitochondria in DCM and the underlying mechanism are unknown. We tested whether BH4 deficiency is involved in DCM and if supplementation restores mitochondrial and heart function in late-stage DCM. The transcription of three BH4 synthesis-regulating genes was compared in cardiac tissues of patients with low or normal ejection fractions (EFs). Forty-eight-week-old type 2 diabetic rats were divided into BH4 treatment and control groups. BH4 levels and the functions of heart and mitochondria were assessed in diabetic or control rats. Sepiapterin reductase knockout (Spr-/-) mice, a model of BH4 deficiency, were used to determine the mechanism of the therapeutic effect of BH4 on DCM. Relative to control rats, diabetic rats, as well as Spr-/- mice, had cardiac contractility, hypertrophic remodeling, and mitochondrial dysfunction, which recovered with BH4 supplementation. BH4 directly bound to CaMKK2 and activated downstream pathways in cardiomyocytes. BH4 is a novel therapeutic target for recovering the left ventricular contractility and structural remodeling in DCM via direct binding and activation of CaMKK2 signaling pathways.

 Date: 2019/3/27 PM4:00~5:00
Speaker: Jin Han,Professor (Department of Physiology, College of Medicine, Inje University)
Title: Physiological role of AMPK alpha activity inhibitory protein in heart and mitochondria
Background and Purpose: Cereblon (CRBN) is an interacting protein with large-conductance calcium-activated potassium channels. A mutation of CRBN causes a mild type of mental retardation in humans. While, recent study suggested its novel function as AMPK inhibitor via direct interaction with AMPK a1 subunit. Disruption of CRBN gene enhanced hepatic AMPK activity and prevents high-fat diet induced obesity and insulin resistance in mice. The aim of study is to figure out the effect of CRBN KO in heart and its mitochondrial function. Method and Results: Eight weeks of Control (CRBN+/+) and CRBN KO (CRBN-/-) models were examined their body weight, heart rate and heart/body ratio. In vivo cardiac functions of animals were assessed by echocardiography. To evaluate mitochondrial function of those animals, cardiac mitochondria of CRBN+/+ and CRBN-/- were isolated then examined their ATP contents and ATP production rate, ROS production rate, oxygen consumption rate (OCR) and membrane potential (ΔΨm). As results, the body weight, heart weight and heart/body ration were not significantly different between CRBN+/+ and CRBN-/- mice. Echocardiography showed enhanced cardiac contractility in CRBN-/- mice based on increased ejection fraction (%) and fractional shortening (%). In their mitochondria, basal ATP contents and substrate/ADP stimulated ATP production rate were significantly higher in CRBN-/- mice than CRBN+/+. In addition, basal H2O2 level and rotenone induced ROS production rates were significantly lower in CRBN-/- mice than CRBN+/+. CRBN KO mice showed higher single cell contractility with higher Ca2+ transient amplitude in isolated left ventricular cardiac myocytes.
Conclusion: Our results suggested that CRBN is an important mitochondrial functional regulator which link cytosol to mitochondrial energy metabolic signaling.
Keyword: Cereblon, cardiac contractility, mitochondrial energy metabolism.

Date: 2019/1/4 PM3:30~4:30
Speaker:富田 泰輔 教授 (東京大学大学院薬学系研究科機能病態学教室 Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Science, The University of Tokyo)
Understanding the molecular/cellular pathology and emerging strategies for Alzheimer disease
 Abstract Body: Aggregated forms of amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, which are pathological hallmarks in the brains of Alzheimer disease (AD) patients. Several lines of evidence suggest that accumulation of Aβ induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, facilitation of the clearance of aggregated Aβ and tau has been highlighted as a plausible therapeutic for AD. In addition, genetic studies in AD implicate the pathological roles of glial cells, such as astrocytes and microglia. We recently identified kallikrein-related peptidase 7 (KLK7) as a novel aggregated Aβ-degrading enzyme secreted from astrocyte, suggesting that astrocyte is a cellular target in AD therapeutics. Moreover, we have developed a novel small compound called photooxygenation catalyst that facilitates the selective degradation of aggregated proteins in vivo. I will discuss with these novel approaches for anti-aggregated proteins against AD.

Date: 2019/1/4 PM5:00~6:00
竹内 英之 准教授 (名古屋大学大学院医学系研究科・機能分子制御学)
O-結合型糖鎖修飾のNotch シグナルにおける重要性~糖鎖による受容体の活性化制御とその異常による先天性疾患
Title: Significance of O-linked glycosylation in Notch signaling~Regulation of Notch signaling by O-linked glycosylation and human congenital disorders
 Notch シグナルは多細胞生物の発生過程や成体の幹細胞など、細胞の運命決定に非常に重要な役割を果たす。
近年の遺伝学および生化学的な研究によって、Notch 受容体自体の O-結合型糖鎖修飾 (O-フコース、O-グルコース、O-GlcNAc) が、巧妙にシグナルの調節に関わっていること、 さらに、これらのO-結合型糖鎖修飾を担う糖転移酵素遺伝子の変異が、Dowling-Degos 病、肢帯型筋ジストロフィー、Adams-Oliver 症候群など様々なヒトの先天性疾患の原因となることが明らかとなってきた。
本講演では、O-結合型糖鎖修飾が Notch 受容体の活性化を制御する分子メカニズムに関する、生化学、構造生物学、そして、ケミカルバイオロジーツールを用いた最新の研究成果を紹介させて頂く。
 Notch signaling plays significant roles for cell-fate decisions during development and adulthood. Recent genetic and biochemical studies revealed that O-linked glycosylation (O-fucose, O-glucose, and O-GlcNAc) on Notch exquisitely regulates its activation and that a number of mutations in the glycosyltransferase genes cause human congenital disorders such as Dowling-Degos disease, Limb-girdle muscular dystrophy, and Adams-Oliver syndrome. I would like to introduce cutting-edge research on the molecular mechanisms by which O-linked glycosylation regulates Notch signaling through multidisciplinary efforts from biochemistry, structural biology, and chemical biology.

Date: 2018/1/30 PM4:00~5:00
Amira Hajirah Abd Jamil (PhD).(Department of Pharmacy, Faculty of Medicine, University of Malaya,KualaLumpur Malaysia・Senior lecturer)
Cardiac substrate metabolism following hypoxia: Role of Peroxisome Proliferated receptor alpha (PPAR)
 The principal substrate used by the normal adult human heart is free fatty acids, the remainder being, predominantly, carbohydrate. During failure, the heart becomes less reliant on fatty acid metabolism, possibly as a result of tissue hypoxia. Therefore, understanding hypoxic adaptation may explain the metabolic changes that occur during the development of heart failure and potential therapeutic advancement. As peroxisome proliferator activated receptor alpha (PPARα) modulates cardiac fatty acid metabolism, we investigated the role of PPARα in cardiac metabolic adaptation to chronic hypoxia. We have reported isolated hearts from chronically hypoxic (11% O2 for 3 weeks) mice were more glycolytic, had reduced PPARα expression and decreased fatty acid metabolism, but had normal function, determined using in vivo cine-MRI. 31P MRS of isolated perfused mouse hearts showed a drop in phosphocreatine (PCr) with hypoxia, but ΔGATP was not altered, indicating that metabolic reprogramming was sufficient to maintain ATP production and contractile function. Increased or decreased PPARα expression, using a high fat diet or PPARα null mice, respectively, prevented metabolic adaptation to hypoxia and caused cardiac dysfunction. Cardiac vascular endothelial growth factor (VEGF), prominent hypoxia-inducible factor (HIF) target, was increased by hypoxia, indicating that HIF may have been involved in metabolic adaption. In order to determine the relationship between HIF and PPARα, HIF was stabilised pharmacologically using FG2216/BIC in HL-1 cardiomyocytes, to show decreased PPARα expression and caused similar metabolic changes to those seen in the in vivo hypoxic heart. We proposed that HIF-mediated downregulation of PPARα is crucial for metabolic adaptation and maintenance of cardiac function during chronic hypoxia.

Date: 2018/1/15 PM4:00~5:30
Speaker:Prof.Jin Han(National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Title:Pharmacological rescue of mitochondria during heart disease
Tetrahydrobiopterin (BH4) has been suggested to regulate cardiac mitochondrial function as a multifunctional cofactor and an antioxidant, an important role in the cardiovascular system. However, its mechanism on transcriptional coactivators such as peroxisome proliferator activated receptor γ coactivator-1 (PGC1) α and AMP-activated protein kinase (AMPK) signaling, major regulators of energy metabolism in heart, is unknown. Aim of this study was to assess the role of BH4 in the PGC1-α and AMPK signaling in the hearts of mammalian animal. Using a sepiapterin reductase (Spr) knockout mouse, a model of BH4 deficiency, we found that BH4 regulates transcription of PGC1-α and phosphorylation of AMPK α and β and the expression of their target proteins involved in mitochondria biogenesis (mtTFA, and ERRα), antioxidant (Prx3 and SOD2) and fatty acid utilization (CD36 and CPTI-M) in the hearts. BH4 can binds to Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) then activates CaMKIV mediated CREB phosphorylation and AMPK phosphorylation in the heart of model mice. Spr KO mice have shown the development of a lethal cardiomyopathy with mitochondrial dysfunction and exogenous BH4 supplementation successfully rescued those phenotypes. These results reveal a novel molecular mechanism of BH4 in the regulation of cardiac energy metabolism and suggest that BH4 has therapeutic potential for the cardiomyopathy.

Date: 2017/10/13 PM3:00~4:30
Speaker:本田 直樹 先生 (京都大学大学院生命科学研究科 特定准教授)

Date: 2017/7/14 PM3:00~4:00
Speaker:田中 智弘 (NIPS リサーチフェロー)
 筋萎縮性側索硬化症(ALS)の進行に伴い、脊髄に存在する運動ニューロン は変性し、標的骨格筋の麻痺を引き起こす。その変性過程において、運動ニューロン は細胞死に先立ち、軸索末端が標的骨格筋から退縮する「除神経(denervation)」 と呼ばれる現象がALS患者、モデルマウスにおいて認められ、運動機能低下の直接的 な原因と考えられている。しかし除神経をターゲットとしたALS治療アプローチには 未解明の点が多く残されていた。今回私たちは、神経―筋インターフェースに存在す る細胞外マトリクス分子が除神経を抑制する可能性を検討し、1)細胞外マトリクス 分子のリモデリングを引き起こす緩徐な運動によってALSモデルマウスの除神経が抑 制されること、2)運動により細胞外マトリクス分子であるラミニンβ2がシナプス 領域特異的に集積し、アクティブゾーンなどシナプス前終末の構造体を安定化するこ とで除神経を遅延させる役割があることを明らかにした。今後、このような細胞外マ トリクス分子を中心とした除神経を抑制・遅延させるメカニズムを解析していくこと で、ALSなど除神経による運動機能低下を抑えるような新たな治療ターゲットの解明 が期待される。

Date: 2017/1/27 PM4:00~5:00
Speaker:Prof. Yoshifumi Yamaguchi (The University of Tokyo)
Title: Toward understanding mechanisms of mammalian hibernation ~ an approach with Syrian golden hamsters
Hibernation is an adaptive strategy to survive cold winter with little or no food. Some of mammals can hibernate to survive during the winter months by suppressing metabolisms and lowering body temperature and heart rate. Since these physiological changes are lethal to most mammals including mouse and human, it is of great interest from both basic sciences and clinical application to understand mechanisms that enable hibernation. Two fascinating topics in the mysteries of hibernation are “seasonal (chronic) body remodeling for hibernation” and “regulation of deep torpor (immobility state with low body temperature) and periodic arousal during hibernation”. We have tackled the topics by examining one of ideal animal models for hibernation research, Syrian golden hamsters (Mesocricetus auratus); they can enter hibernation throughout the year irrespective of seasons when exposed to a short day photoperiod and cold ambient temperatures under laboratory conditions. In this seminar, I will introduce our recent findings and discuss how hamsters achieve proper hibernation.

Date: 2016/11/25 PM5:00~6:00
Speaker:成瀬 恵治 教授(Prof. Keiji Naruse)
Title: メカノメディスン:メカノトランスダクション研究とその臨床応用
 我々の体は外界からだけではなく体内においても様々な力学的・機械的刺激(メカニカルストレス)を受容し、応答することで正常な生理 機能を維持している.メカニカルストレスの受容応答機構は細胞分裂、発生過程、臓器機能発現など広範な時空間スケールにわたる生理機 能の調節に寄与しており、メカニカルストレス受容応答機構の破綻が様々な病態に関与していることを示唆するエビデンスが集積されてき た.メカノセンサー分子→細胞→組織→臓器→個体レベルでの縦糸的研究に各種臓器の疾患という横糸的研究を加えた布陣をとり、メカノ バイオロジーを切口とした病態解明を基に、新規治療法を開発するメカノ医療(メカノメディスン)の確立を目指し、これまでに数々の新 規研究方法や研究システムを開発し問題を解決してきた. 本講演ではメカノバイオロジーに関する基礎医学的研究、特にメカニカルストレス受容機構を概説し、その研究過程で派生した再生医療( 自己集合化ペプチドを用いた3次元培養+メカニカルストレス負荷システム)・生殖補助医療(マイクロ流路良好運動精子分離システム・ス トレッチ刺激負荷受精卵培養システム)への展開を紹介する。

Date: 2016/11/25 PM4:00~5:00
高井 章 教授(Prof. Akira Takai)
所属:旭川医科大学 生理学講座 自律機能分野
 視覚遠近調節を司る毛様体筋は典型的な副交感神経支配の平滑筋組織の一つである。この筋には、膜表面のM3型ムスカリン受容体刺激に応 じて開口する、単位コンダクタンスが100 fS と35 pSと大きく異なる2種類の非選択性陽イオンチャネル(NSCCSとNSCCL)が存在する。そのう ち、いわゆるstore-operated Ca2+ channel (SOC)様の性質を示すNSCCSについては、安定的な視覚焦点合わせに重要な筋収縮持続相の維持 に必要な細胞外からのCa2+の流入経路として機能することが予想されてきた。しかし、実験に供しうる十分な数の健常な単離毛様体筋細胞 を得ることが難しいことが制約となり、NSCCSの分子実体の解明はなかなか進まなかった。最近われわれはコラゲナーゼ処理とPercoll密度 勾配遠心分離によりウシ毛様体筋組織から平滑筋細胞を高純度に取り出す方法を開発した。それにより調整した単離筋細胞を用いてsiRNA法 などによる実験をおこなったところ、SOCの本体として注目されているSTIM1/Orai1とNSCCSとの関連を強く示す知見が得られた。
 In bovine ciliary muscle (BCM), stimulation of M3-muscarinic receptors opens a non-selective cation channel (NSCC) with a ve ry low unitary conductance (100 fS), which serves as the major pathway for Ca2+ entry during sustained contraction. The mole cular entity of this channel has been unknown, mainly because of the technical difficulty of obtaining BCM cells with suffic ient purity. Recently we developed a new method which has enabled to obtain BCM cells with unprecedented quality and amount and applied it to examine the existence and localization of TRPCs, STIM1 and Orai1. The ciliary body dissected from bovine e ye was treated with collagenase, and the dispersed cells were subjected centrifugation through a discontinuous Percoll densi ty-gradient of 1.050 and 1.060 g/mL. Cells were then collected from the 1.050/1.060 interface and cultured for 1-3 days befo re use. In the cultured BCM cells, carbachol (2 μM) evoked a phasic and tonic increase of [Ca2+]i monitored with fluo-4 flu orophore. These responses were clearly observed in 5 × 106 cells obtained by the single-step centrifugation procedure. Part ial knockdown of STIM1 by siRNA resulted in a 60% reduction of the tonic component of the carbachol-induced rise of [Ca2+]i.

Date: 2016/4/22 PM5:00~6:00
Speaker:金保 安則 教授(Prof. Yasunori Kanaho) (筑波大学医学医療系(生命医科学域)生理化学研究室 (Dept. of Physiological Chemistry, Faculty of Medicine, Univ. of Tsukuba) )
Title: 低分子量G蛋白質Arf6の意外な病理学的および生理学的機能
(Unexpected pathological and physiological significance of the small G protein Arf6)
 低分子量G蛋白質のArf6は、シグナル伝達系において分子スイッチとして機能しており、細胞レベルで細胞膜ダイナミクスに関連した細胞機 能を制御している。我々は、1999年にArf6がリン脂質キナーゼのPIP5Kの活性をして細胞膜形態を制御するという非常に興味深い発見をして 以来、Arf6の個体レベルでの生理学的および病理学的機能への関与について解析を進めており、Arf6シグナル伝達をターゲットとした創薬 開発を模索している。本セミナーでは、これらの点について、極めて新規な知見を紹介し、議論したい。
 The small G protein Arf6 functions as a molecular switch in various signal transduction systems and regulates membrane dynam ics-based cellular events. In 1999, we found a novel function of Arf6 that this molecule regulates membrane dynamics through the activation of the lipid kinase PIP5K. Thereafter, we have been focusing to analyze the physiological and pathological f unctions of Arf6, and exploring the new drugs targeting Arf6 signaling. In this seminar I show our recent progress about pat hophysiological functions of Arf6 and discuss on these data.

Date: 2015/12/12 PM 5:30~PM 6:30
Speaker:Prof. Motonari UESUGI(
京都大学 物質-細胞統合システム拠点 副拠点長・教授)
 人間の歴史の中で、生理活性小分子化合物は医薬品、農薬、基礎生物学研究のツールとして利用されてきました。今回の講演では、基礎生 物学ツールの紹介に加えて、生理活性化合物の第4の利用法として、細胞治療を助ける小分子化合物を紹介します。これまでの古典的な医 薬品の枠にとらわれなければ、化合物にはさまざまな可能性や未来が想像できます。新しいサイズ、新しいカタチ、新しい作用メカニズム などを考えれば、化合物の新しい使い方や未来が垣間見えます。

Date: 2015/12/12 PM 4:00~PM 5:00
Speaker:Prof. Yasuo MORI(
京都大学大学院工学研究科 合成・生物化学専攻  生物化学講座 分子生物化学分野・教授)
Relationships of us aerobic living organisms with O2 are more delicate than we think
 O2 is essential for aerobic organisms. While this characterization for O2 appears almighty in biology, it is not enough to describe delicate significance of O2 in vivo. When O2 is highly required to elicit metabolic activity through ATP productio n in cells and organs, it is very true that their survival is easily endangered by disruption of O2 supply (hypoxia). Howe ver, recently, evidence has been accumulated that hypoxia can support certain states of cells and organs. In addition, if s urplus O2 is provided to cells and organs in the body (hyperoxia), it leads to the production of reactive species responsibl e for oxidative stress that influences and often dysregulates downstream cellular signals. Today, I would like to introduce some of our works on TRP channels that act as sensors for O2 and reactive oxygen species and also as actuators to initiate downstream electrical/chemical signals, and discuss about how ‘appropriate’ levels of O2 are attained via TRP channels.

Date: 2015/8/10 PM 2:00~PM 3:00
Speaker:Prof. Yukihiro AKAO(United Graduate School of Drug Discovery and Medical Information Sciences, Gihu University)
MicroRNA regulates the cancer-specific Warburg effect through targeting splicer PTB1
 ①The Warburg effect has been well known as a feature of cancer specific metabolism. One of the key molecule of Warburg effect is polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of the limiting enzymes pyruvate kinase muscle 1 and 2 (PKM1 and PKM2). Recently, we focus on the functions of PTB1 and PTB1-associated microRNAs (miRs). In this seminar, I demonstrate a critical role of miR-1 and -133b on Warburg effect in colorectalcancer cells. ②We newly found that the mechanisms of TRAIL-resistance consist of decrease in the expression level of DR5 and malfunction of its recruitment on the cell surface. Interestingly, α-mangostin which is one of the xanthone derivatives canceled the resistance by increasing the expression level of DR5 through down-regulation of miR-133b and effectively induced DR5 to cancer cell surface membrane in TRAIL-resistant DLD-1 cells. I will discuss concerning the TRAIL-resistance and its attenuation.

Date: 2015/4/21 PM 5:00~PM 6:00
Speaker:Dr. Shigehiro OHDO(Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University)
Drug discovery on based on molecular clock
 Behavioral and physiological rhythms in most living organisms are regulated by the molecular clock system. Alterations in molecular clocks works are associated with various diseases such as cancer, metabolic syndrome, and hypertension. Currently, treatment for such diseases remains unsatisfactory, resulting in unmet medical needs. Hepatocellular carcinoma (HCC) is one such disease with unmet medical needs. Chronic inflammatory and HCC are induced by infection of hepatitis B and C viruses. Interferon (IFN) therapy reduce HCC. However, existing therapy methods are insufficient for correcting chronic hepatitis and HCC. Therefore, we investigated the influence of molecular clock function on the development of chronic inflammatory and HCC. The 24-h expression of clock genes and Ccrf were altered in liver at 14 weeks after treatment of diethylnitrosamine (DEN). The microarray analysis in Ccrf knockdown hepatic cells showed the alteration of pathway in carcinoma and cell cycle. Addition, function of Ccrf protein was regulated the inflammatory signal. The present time, high throughput chemical screening has been performed for discovery of Ccrf inhibitor. Molecular clock function is very important as a new target in the treatment of Chronic inflammatory and HCC.

Date: 2015/3/16 PM 5:00~PM 6:00
Speaker: Dr.
Yoshito KUMAGAI ( Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba)
Electrophiles-mediated modulation of redox signal transduction pathways regulated by reactive sulfur species
 Electrophiles react readily with protein thiolate ions, resulting in protein adduct formations. For example, endogenous electrophiles covalently modify sensor proteins with reactive thiols, leading to reduction of those activities, thereby activating effector molecules (e.g., kinases, transcription factors). We found that exogenous electrophiles in the environment activate redox-signal transduction pathways through chemical modification of the sensor protein thilate ions; however, such reactive chemicals disrupt these signaling, resulting in occurrence of toxicity at higher concentrations. More interestingly, environmental electrophiles-mediated these events are regulated by reactive sulfur species through those sulfur adduct formations. In this lecture, I will introduce our recent findings associated with modulation of redox-signal transduction pathways mediated by environmental electrophiles and also discuss biological significance of reactive sulfur species in repression of the activation of signal transduction pathways and toxicity.

Date: 2015/3/16 PM 4:00~PM 5:00
Speaker: Dr.Takaaki AKAIKE(Department of Environmental Health Sciences and Molecular Toxicology Tohoku University Graduate School of Medicine )
Title: Paradigm-shifting protein modifications in redox signal regulation

 Many organisms conduct high-level vital activities by energy metabolism that uses the chemical reactivity of molecular oxygen (oxidation-reduction: redox activity). The redox-based cellular signaling is now thought to be modulated by various protein effector molecules, as affected critically by reactive oxygen species via translational and post-translational pathways. Through this seminar, I will shed light on a previously unrecognized protein modification, i.e., protein S-polythiolation, as a paradigm-shifting discovery evolving from the changing concept of redox biology, as well as redox pathology known as oxidative stress.

Date: 2015/2/24 AM 10:00~AM11:00
Speaker: Dr.Tomoya ITO(Laboratory of Molecular Biology (Mori laboratory),
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University)
Title : Identification of a novel protein-coding gene OGU1 regulatingintracellular transport of TRPC channels
 Thousands of transcribed long RNAs have been discovered in mammalian intergenic region. Although recent study indicates that these intergenic transcripts are predicted to be long noncoding RNA (lncRNA) gene candidates, biologically functional entities of these most gene candidates remain elusive. We revealed that lncRNA locus OGU1 (osteogenesis up-regulating transcript 1) is indeed endogenously translated into a small protein that activates TRP (transient receptor potential) channels. Moreover, our present study suggests that OGU1 recruits TRPC channels to the cell surface by regulating unconventional intracellular trafficking.

Date: 2015/1/15 PM 2:00~PM 3:00
Speaker: Dr.Hiroyuki KOBAYASHI(
Molecular Pharmacology Unit (Michel Bouvier), Institut de Recherche en Immunologie et en Cancérologie, Université d e Montréal)
Title: GPCR interacting proteins and signaling diversity – Studies based on BRET assay

 G protein-coupled receptor (GPCR) is one of the largest families of proteins transducing extracellular signals through cellu lar membrane. Although GPCRs are described as ‘ON’ or ‘OFF’ switches in the classical two state model, recent studies revealed that one GPCR can activate many GPCR-dependent/independent signaling pathways simultaneously, but limit the pathway s it activates depending on the functional states determined by ligand binding and/or signalosome formation. This concept th at GPCR can change the downstream signal dynamically depending on the receptor microenvironment, is called “Ligand-biased s ignaling”, and creates new paradigm in the receptor research and drug design. We are aiming at elucidating the structural d eterminants of this GPCR signaling diversity, and developed assay tools based on BRET, bioluminescence resonance energy tran sfer, techniques.

Date: 2014/12/22 PM 5:00~PM 6:00
Speaker: Dr. Supachoke Mangmool
(Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Thailand)
Title: Sustained β-adrenergic receptor stimulation mediates cardiac insulin resistance in a PKA-dependent manner

 Insulin resistance is a condition in which there are defects in the insulin actions to induce tissue glucose uptake. Overstimulation of β-adrenergic receptors (βARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which βARs overstimulation affect insulin resistance in the heart are incompletely understood. We examine the mechanism for insulin resistance regulated by overstimulation of βARs. In this study, we show that sustained βAR stimulation with isoproterenol (ISO) showed the inhibition of insulin-induce glucose uptake and glucose transporter-4 (GLUT4) expression is mediated by the β2AR subtype in cardiomyocytes and heart tissue. Moreover, ISO stimulation attenuated insulin-induced GLUT4 translocation in β2AR-overexpressing HEK-293 cells. Overstimulation of βARs plays a key role in the enhancement of insulin resistance in the heart through cyclic adenosine monophosphate (cAMP)-dependent and protein kinase A (PKA)-dependent pathways. Treatment with β-blockers is able to antagonize the action of ISO-mediated insulin resistance in the heart. The essential role for βARs and identification of the molecular mechanism of βARs on the induction of insulin resistance in the heart advances our understanding, leading to a new therapeutic target for heart diseases.

Date: 2014/10/28 PM 5:30~PM 6:30
Speaker: Prof. Hirofumi KAI(Dept. of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University
Title:Beneficial effects and their molecular mechanisms of specific pulse width mild electrical stress as physical medicine

 Electrical current at physiological strength has been used as folk medicine and applied as a therapeutic approach for various diseases.
Recently, we have shown that specific pulse width mild electrical stress (MES : duration : 0.1 millisecond, 55 pulse per second, voltage : 1~2 V/cm) has positive impact on organisms. We have shown that together with heat shock, which elevated the level of heat shock protein 72 (Hsp72), MES attenuated hepatic ischemia/reperfusion injury in mice, ameliorated the diabetic phenotype and protected pancreatic β-cells in diabetes mouse model, reduced inflammatory markers in healthy male subjects, and decreased the proteinuria and renal inflammation in Alport syndrome mouse model. In the Alport model, MES was shown to activate not only PI(3)K-Akt pathway but also the p38 MAPK signaling pathway. Recently, we have found that MES activated p53, a tumor suppressor known for its cellular protective functions via a network of signaling pathways, leading to G2 phase arrest, and that MES affected LKB1-AMPK signaling, which in turn increases stress resistance and suppresses fat accumulation in C. elegans. These findings add to our growing knowledge of the underlying mechanisms of the effects of optimized mild electrical stimulation as physical medicine.

Date: 2014/9/12 PM 4:00~PM 5:00
Speaker: Dr.Yasunori KANAHO(Dept. of Physiological Chemistry, Faculty of Medicine, Univ. of Tsukuba)
Title:Unexpected physiological significance of the small G protein Arf6

 The small G protein Arf6 functions as a molecular switch in various signal transduction systems and regulates membrane recycling. In 1999, we found a very interesting novel function of Arf6 that this molecule regulates membrane dynamics through the activation of the lipid kinase PIP5K. Thereafter, we have been focusing to analyze the physiological functions of Arf6 and its involvement in pathophysiology at the whole animal level. In this seminar I show our recent progress about pathophysiological functions of Arf6.

Date: 2014/9/12 PM 5:15~PM 6:15
Speaker: Dr.Shinichi HOSHINO(Graduate School of  Pharmaceutical Sciences, Nagoya City University)
Title:Mechanism of mRNA decay and regulation of gene expression

 mRNA decay plays a pivotal role in gene expression.  Shortening of the 3’poly(A) tail, called deadenylation, is the first and the late-limiting step in the decay of general mRNA.  We have previously shown that translation termination acts as a trigger of mRNA decay and proposed a model for the translation termination-coupled mRNA decay: after translation termination, the termination factor eRF3 dissociates from mRNA, which triggers recruitment of the deadenylases, Pan2-Pan3 and Caf1-Ccr4, to initiate mRNA decay.  In this seminar, I will talk about novel regulatory mechanisms of gene expression, which target deadenylatio.

Date: 2014/6/23 PM 4:00~PM 5:00
Speaker: Dr. Gentaro IRIBE
(Cardiovascular Physiology, Okayama Univ.)
Title:Physiological implications of mechanosensitive response of mitochondria in cardiomyocytes
 Myocardium contracts against ventricular wall stretch. Myocardial contraction requires ATP that is produced by mitochondrial electron transport system. Mitochondrial ATP production process is also known as one of the sources of reactive oxygen species (ROS), which are toxic molecules, but also important physiological regulators of intracellular signaling pathways. We previously found that myocardial stretch increases Ca2+ spark, which is local and spontaneous Ca2+ releasing event from sarcoplasmic reticulum. Our recent findings indicate that stretch-induced increase in mitochondrial ROS production is associated with these responses.

Date: 2014/5/20 PM 2:00~PM 3:00
Speaker: Dr. Hidetoshi SAITOH(Dept of Molecular and System Pharmacology, Kyusyu Univ.)

Title:Role of P2Y purinergic receptors in microglia
Microglia are constantly surveying the brain parenchyma. Incidents in the brain rapidly activate microglia and activated microglia induce chemotaxis, phagocytosis and inflammatory responses. Extracellular nucleotides are signaling molecules used by microglia to sense adverse physiological conditions. They act through several purinoceptors in microglia. We have found that P2Y6 receptor enhances microglial macropinocytosis which regulated by protein kinase D, and P2Y12 receptor elicit transient intracellular calcium increases which leads to the de novo production of several chemokines. Each findings are now associated with amyloid beta uptake by microglia and microglial P2Y12 receptor mediated development of neuropathic pain.

Date:2014/2/28 PM 1:30~PM 2:30
Speaker: Dr.Kenji TAGO (Dept of Biochem, Div of Structural Biochem, Jichi Med Univ)
Title:Functional analysis of atypical Ras family protein in oncogenic signal
 A small GTPase κB-Ras was identified as a Ras family protein inhibiting a transcription factor NF-κB. We previously clarified the molecular mechanism how κB-Ras inhibits the NF-κB activation. In the current study, we found that κB-Ras harbors the critical roles in Ras (G12V)-caused oncogenic signals. Furthermore, we purified κB-Ras-containing protein complexes, and identified novel κB-Ras binding proteins including TRB3, SmgGDS, DDB1, NONO. Our study suggests that κB-Ras could contribute to the oncogenic signaling pathway through the interaction with these binding proteins.

Date:2014/1/7 PM 3:00~PM 4:00
Speaker: Takuro Tomita (Assistant Professor, Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University)
Title:Receptor-activated cation channels and thier physiological importances

Date:2014/1/7 PM 4:00~PM 5:00
Speaker: Akiyuki Nishimura (Postdoc Fellow, Department of Molecular Medicine, Cornell University, USA)
Title:Identification of novel prenyl-parmitoyl modification of Cdc42 and its functional role
   Copylight(C)2014 NIPS All Right Reserved.