辛洪波
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- 姓名:辛洪波
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学术头衔:
博士生导师
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学科领域:
药物化学
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辛洪波,1991年7月获北京大学医学部药理学博士学位,1991年9月至1993年9月任北京大学医学部药理学系任讲师,1993年10月至1998年10月在美国范德比尔特大学(Vanderbilt University)分子生物学系从事博士后研究,1998年11月至1999年11月晋升为讲师,1999年12月至2000年6月为美国宾夕法尼亚大学(University of Pennsylvania)动物生物学系研究助理教授(Research Assistant Professor),2000年7月至2001年6月为美国康奈尔大学(Cornell University) 生物医学科学系高级研究员(Senior Research Associate),2000年7月至2005年12月为美国康奈尔大学生物医学科学系生理学和分子生物学助教授 (Assistant Professor),博士生导师, 2005年11月至今为四川大学国家生物治疗重点实验室教授, 博士生导师。现为美国生物物理学会和美国糖尿病学会会员。至今已发表科研论文40篇(其中第一作者24篇),其论文总影响因子为120余点,论文引用力为500 余次。在国內学习及工作期间,主要从事心血管药物特别是抗心侓矢常药物的药理学研究,其主要成果曾由中国卫生部主办的"医学论坛报"作了专题报道。1993年10月赴美深造,主要从事心肌,骨骼肌和平滑肌肌质网钙释放通道(calcium release channels /ryanodine receptors, RyRs) 的生理学,生物化学和分子生物学研究,师从美国Vanderbilt大学的国际知名生物化学家Sidney Fleischer教授(RyRs的发现者),其论文曾在国际知名学术期刊如"自然 (Nature)","生物化学杂志 (Journal of Biological Chemistry)"等发表。此外,还就胰岛 细胞内质网钙动员对胰岛素分泌的影响进行了系统的研究,其结果正在整理中。现已申报国际专利两项,其中"组织或细胞特异性基因敲除载体构建 (Vectors for conditional gene inactivation)"专利技术能迅速、有效、低成本地用于研究小鼠的基因功能,由于小鼠具有与人类基因组的高度同源性,该项技术将为研究小鼠及人体的发生,发育及发展,为人类疾病的诊断及治疗和新药开发提供重要的工具。
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辛洪波, Hong-Bo Xin, Anthony P. Timermanj, Hitoshi Onoue, Gregory J. Wiederrecht*, and Sidney Fleischer
Vol. 214, No.1, 1995, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,-0001,():
-1年11月30日
The ryanodine receptor (RyR)/calcium release channel isolated from skeletal muscle terminal cisternae (TC) of sarcoplasmic reticulum (SR) is tightly associated with FK506 binding protein of 12.0 kDa (FKBPI2) (Jayaraman et al., (1992) J. BioI. Chem. 267, 9474-9477). In this study, we describe a new method of affinity chromatography for purifying the RyR from skeletal muscle SR based on: 1) its tight association with FKBP12; and 2) the finding that bound FKBP on the RyR can be exchanged with soluble FKBPI2 (Timerman et al., (1995) J. Biol. Chem. 270, 2451-2459). Soluble glutathione S-transferase/FKBPl 2 (GST/FKBP12) fusion protein was first exchanged with bound FKBPI 2 on the RyR of TC. The TC were then solubilized with CHAPS and the complex of RyR-GST/FKBPI2 was specifically adsorbed by glutathione Sepharose 4B and then eluted with glutathione. The RyR, purified by this method, has similar characteristics by SDS-PAGE, radioligand binding and immuno-reactivity as the RyR purified by multiple sequential column chromatography.
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【期刊论文】Selective Binding of FKBP12.6 by the Cardiac Ryanodine Receptor*
辛洪波, Anthony P. Timerman‡§, Hitoshi Onoue‡§¶, Hong-Bo Xin‡, Sebastian Barg‡, Julio Copello‡, Greg Wiederrechti, and Sidney Fleischer‡**
Vol. 271, No.34, Issue of August 23, pp. 20385-20391, 1996,-0001,():
-1年11月30日
The calcium release channels (CRC)/ryanodine receptors of skeletal (Sk) and cardiac (C) muscle sarcoplasmic reticulum (SR) are hetero-oligomeric complexes with the structural formulas (ryanodine recepter (RyR)1 protomer)4(FKBP12)4 and (RyR2 protomer)4(FKBP12.6)4, respectively, where FKBP12 and FKBP12.6 are isoforms of the 12-kDa receptor for the immunosuppressant drug FK506. The sequence similarity between the RyR protomers and FKBP12 isoforms is 63 and 85%, respectively. Using 35S-labeled FKBP12 and 35S-labeled FKBP12.6 as probes to study the interaction with CRC, we find that: 1) analogous to its action in skeletal muscle sarcoplasmic reticulum (SkMSR), FK506 (or analog FK590) dissociates FKBP12.6 from CSR; 2) both FKBP isoforms bind to FKBP-stripped SkMSR and exchange with endogenously bound FKBP12 of SkMSR; and 3) by contrast, only FKBP12.6 exchanges with endogenously bound FKBP12.6 or rebinds to FKBP-stripped CSR. This selective binding appears to explain why the cardiac CRC is isolated as a complex with FKBP12.6, whereas the skeletal muscle CRC is isolated as a complex with FKBP12, although only FKBP12 is detectable in the myoplasm of both muscle types. Also, in contrast to the activation of the channel by removal of FKBP from skeletal muscle, no activation is detected in CRC activity in FKBPstripped CSR. This differential action of FKBP may reflect a fundamental difference in the modulation of excitation-contraction coupling in heart versus skeletal muscle.
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辛洪波, Terence Wagenknecht, * Robert Grassucci, * Jon Berkowitz, * Gregory J. Wiederrecht
Biophysical Journal Volume 70 April 1996 1709-1715,-0001,():
-1年11月30日
A 1 2-kDa immunophilin (FKBP12)is an integral component of the skeletal muscle ryanodine receptor (RyR). The RyR is a hetero-oligomeric complex with structural formula (FKBP)4(Ryrl)4, where Ryrl is the 565-kDa product of the Ryrl gene. To aid in the detection of the immunophilin's location in the receptor, we exchanged the FKBP12 present in RyR-enriched vesicles derived from sarcoplasmic reticulum with an engineered construct of FKBP12 fused to glutathione S-transferase and then isolated the complexes. Cryoelectron microscopy and image averaging of the complexes (in an orientation displaying the RyR's fourfold symmetry) revealed four symmetrically distributed, diffuse density regions that were located just outside the boundary defining the cytoplasmic assembly of the RyR. These regions are attributed to the glutathione transferase portion of the fusion protein because they are absent from receptors lacking the fusion protein. To more precisely define the location of FKBP1 2, we similarly analyzed complexes of RyR containing FKBP1 2 itself. Apparently some FKBP is lost during purification or storage of the RyR because, to detect the receptor-bound immunophilin, it was necessary to add FKBP1 2 to the purified receptor before electron microscopy. Averaged images of these complexes showed a region of density that had not been observed previously in images of isolated receptors, and its position, along the edges of the transmembrane assembly, agreed with the position of the FKBP12 deduced from the experiments with the fusion protein. The proposed locations for FKBP1 2 are about 10 nm from the transmembrane baseplate assembly that contains the ion channel of the RyR.
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辛洪波, Terence Wagenknecht‡§, Michael Radermacher‡§, Robert Grassucci‡, Jon Berkowitz‡, Hong-Bo Xin¶, and Sidney Fleischer¶
Vol. 272, No.51, Issue of December 19, pp. 32463-32471, 1997,-0001,():
-1年11月30日
Isolated skeletal muscle ryanodine receptors (RyRs) complexed with the modulatory ligands, calmodulin (CaM) or 12-kDa FK506-binding protein (FKBP12), have been characterized by electron cryomicroscopy and three-dimensional reconstruction. RyRs are composed of 4 large subunits (molecular mass 565 kDa) that assemble to form a 4-fold symmetric complex that, architecturally, comprises two major substructures, a large ('80% of the total mass) cytoplasmic assembly and a smaller transmembrane assembly. Both CaM and FKBP12 bind to the cytoplasmic assembly at sites that are 10 and 12 nm, respectively, from the putative entrance to the transmembrane ion channel. FKBP12 binds along the edge of the square-shaped cytoplasmic assembly near the face that interacts in vivo with the sarcolemma/transverse tubule membrane system, whereas CaM binds within a cleft that faces the junctional face of the sarcoplasmic reticulum membrane at the triad junction. Both ligands interact with a domain that connects directly to a cytoplasmic extension of the transmembrane assembly of the receptor, and thus might cause structural changes in the domain which in turn modulate channel gating.
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【期刊论文】Cryoelectron Microscopy and Image Analysis of the Cardiac Ryanodine Receptor*
辛洪波, Manjuli Rani Sharma‡§, Pawel Penczek‡¶, Robert Grassucci‡, Hong-Bo Xini, Sidney Fleischeri, and Terence Wagenknecht‡**
Vol. 273, No.29, Issue of July 17, pp. 18429-18434, 1998,-0001,():
-1年11月30日
The three-dimensional structure of the cardiac muscle ryanodine receptor (RyR2) is described and compared with its skeletal muscle isoform (RyR1). Previously, structural studies of RyR2 have not been as informative as those for RyR1 because optimal conditions for electron microscopy, which require low levels of phospholipid, are destabilizing for RyR2. A simple procedure was devised for diluting RyR2 (in phospholipid-containing buffer) into a lipid-free buffer directly on the electron microscope grid, followed by freezing within a few seconds. Cryoelectron microscopy of RyR2 so prepared yielded images of sufficient quality for analysis by single particle image processing. Averaged projection images for RyR2, as well as for RyR1, prepared under the same conditions, were found to be nearly identical in overall dimensions and appearance at the resolution attained, '30
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辛洪波, Hong-Bo Xin, Kevin Rogers, Ying Qi, Takashi Kanematsu, and Sidney Fleischer‡
Vol. 274, No.22, Issue of May 28, pp. 15315-15319, 1999,-0001,():
-1年11月30日
FK506-binding protein (FKBP12) has been found to be associated with the skeletal muscle ryanodine receptor (RyR1) (calcium release channel), whereas FKBP12.6, a novel isoform of FKBP, is selectively associated with the cardiac ryanodine receptor (RyR2). For both RyRs, the stoichiometry is 4 FKBP/RyR. Although FKBP12.6 differs from FKBP12 by only 18 of 108 amino acids, FKBP12.6 selectively binds to RyR2 and exchanges with bound FKBP12.6 of RyR2, whereas both FKBP isoforms bind to RyR1 and exchange with bound FKBP12 of RyR1. To assess the amino acid residues of FKBP12.6 that are critical for selective binding to RyR2, the residues of FKBP12.6 that differ with FKBP12 were mutated to the respective residues of FKBP12. RyR2 of cardiac sarcoplasmic reticulum, prelabeled by exchange with [35S]FKBP12.6, was used as assay system for binding/exchange with the mutants. The triple mutant (Q31E/N32D/F59W) of FKBP12.6 was found to lack selective binding to the cardiac RyR2, comparable with that of FKBP12.0. In complementary studies, mutations of FKBP12 to the three critical amino acids of FKBP12.6, conferred selective binding to RyR2. Each of the FKBP12.6 and FKBP12 mutants retained binding to the skeletal muscle RyR1. We conclude that three amino acid residues (Gln31, Asn32, and Phe59) of human FKBP12.6 account for the selective binding to cardiac RyR2.
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【期刊论文】FKBP Binding Characteristics of Cardiac Microsomes from Diverse Vertebrates
辛洪波, Loice H. Jeyakumar, * Leomar Ballester, * Dong S. Cheng, * James O. McIntyre, * Paul Chang, † Harold E. Olivey, ‡ Louise Rollins-Smith, § Joey V. Barnett, ‡, ¶ Katherine Murray, ¶ Hong-Bo Xin, \ and Sidney Fleischer*,
Biochemical and Biophysical Research Communications 281, 979-986 (2001),-0001,():
-1年11月30日
FK506 binding protein (FKBP) is a cytosolic receptor for the immunosuppressive drug FK-506. The common isoform, FKBP12, was found to be associated with the calcium release channel (ryanodine receptor 1) of different species of vertebrate skeletal muscle, whereas 12.6, a novel FKBP isoform was found to be associated with canine cardiac ryanodine receptor (ryanodine receptor 2). Until recently, canine cardiac sarcoplasmic reticulum was considered to be the prototype for studying heart RyR2 and its interactions with FKBP. In this study, cardiac microsomes were isolated from diverse vertebrates: human, rabbit, rat, mice, dog, chicken, frog, and fish and were analyzed for their ability to bind or exchange with FKBP isoforms 12 and 12.6. Our studies indicate that RyR2 from seven out of the eight animals contain both FKBP12 and 12.6. Dog is the exception. It can now be concluded that the association of FKBP isoforms with RyR2 is widely conserved in the hearts of different species of vertebrates.
FKBP isoforms, ryanodine receptors, heart, human, rabbit, rat, mouse, dog, isoform-specific antibodies.,
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【期刊论文】Smooth muscle expression of Cre recombinase and eGFP in transgenic mice
辛洪波, H.-B. XIN, * K.-Y. DENG, * M. RISHNIW, G. JI, AND M. I. KOTLIKOFF
Physiol Genomics 10: 211-215, 2002,-0001,():
-1年11月30日
We report the generation of transgenic mice designed to facilitate the study of vascular and nonvascular smooth muscle biology in vivo. The smooth muscle myosin heavy chain (smMHC) promoter was used to direct expression of a bicistronic transgene consisting of Cre recombinase and enhanced green fluorescent protein (eGFP) coding sequences. Animals expressing the transgene display strong fluorescence confined to vascular and nonvascular smooth muscle. Enzymatic dissociation of smooth muscle yields viable, fluorescent cells that can be studied as single cells or sorted by FACS for gene expression studies. smMHC/Cre/eGFP mice were crossed with ROSA26/lacZ reporter mice to determine Cre recombinase activity; Cre recombinase was expressed in all smooth muscles in adult mice, and there was an excellent overlap between expression of the recombinase and eGFP. Initial smooth muscle-specific expression of fluorescence and Cre recombinase was detected on embryonic day 12.5. These mice will be useful to define smooth muscle gene function in vivo in mice, for the study of gene function in single, live cells, and for the determination of gene expression in vascular and nonvascular smooth muscle.
bicistronic construct, fluorescence-activated cell sorting, angiogenesis, gene expression
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【期刊论文】FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells
辛洪波, Yong-Xiao Wang, Yun-Min Zheng, Qi-Bing Mei, Qinq-Song Wang, Mei Lin Collier, Sidney Fleischer, Hong-Bo Xin, and Michael I. Kotlikoff
Am J Physiol Cell Physiol 286: C538-C546, 2004.,-0001,():
-1年11月30日
Intracellular Ca2+ release through ryanodine receptors (RyRs) plays important roles in smooth muscle excitation-contraction coupling, but the underlying regulatory mechanisms are poorly understood. Here we show that FK506 binding protein of 12.6 kDa (FKBP12.6) associates with and regulates type 2 RyRs (RyR2) in tracheal smooth muscle. FKBP12.6 binds to RyR2 but not other RyR or inositol 1,4,5-trisphosphate receptors, and FKBP12, known to bind to and modulate skeletal RyRs, does not associate with RyR2. When dialyzed into tracheal myocytes, cyclic ADP-ribose (cADPR) alters spontaneous Ca2+ release at lower concentrations and produces macroscopic Ca2+ release at higher concentrations; neurotransmitterevoked Ca2+ release is also augmented by cADPR. These actions are mediated through FKBP12.6 because they are inhibited by molar excess of recombinant FKBP12.6 and are not observed in myocytes from FKBP12.6-knockout mice. We also report that force development in FKBP12.6-null mice, observed as a decrease in the concentration/tension relationship of isolated trachealis segments, is impaired. Taken together, these findings point to an important role of the FKBP12.6/RyR2 complex in stochastic (spontaneous) and receptormediated Ca2+ release in smooth muscle.
FK506 binding protein 12., 6, ryanodine receptor type 2, calcium sparks, calcium-activated chloride currents
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辛洪波, Yun-Min Zheng a, Qi-Bing Meia, Qing-Song Wang a, Iskandar Abdullaev a, F. Anthony Lai b, Hong-Bo Xin c, Michael I. Kotlikoff c, Yong-Xiao Wang a, ∗
Cell Calcium 35(2004)345-355,-0001,():
-1年11月30日
The cellular and molecular processes underlying the regulation of ryanodine receptor (RyR) Ca2+ release in smooth muscle cells (SMCs) are incompletely understood. Here we show that FKBP12.6 proteins are expressed in pulmonary artery (PA) smooth muscle and associated with type-2 RyRs (RyR2), but not RyR1, RyR3, or IP3 receptors (IP3Rs) in PA sarcoplasmic reticulum. Application of FK506, which binds to FKBPs and dissociates these proteins from RyRs, induced an increase in [Ca2+]i and Ca2+-activated Cl− and K+ currents in freshly isolated PASMCs, whereas cyclosporin, an agent known to inhibit calcineurin but not to interact with FKBPs, failed to induce an increase in [Ca2+]i. FK506-induced [Ca2+]i increase was completely blocked by the RyR antagonist ruthenium red and ryanodine, but not the IP3R antagonist heparin. Hypoxic Ca2+ response and hypoxic vasoconstriction were significantly enhanced in FKBP12.6 knockout mouse PASMCs. FK506 or rapamycin pretreatment also enhanced hypoxic increase [Ca2+]i, but did not alter caffeine-induced Ca2+ release (SR Ca2+ content) in PASMCs. Norepinephrine-induced Ca2+ release and force generation were also markedly enhanced in PASMCs from FKBP12.6 null mice. These findings suggest that FKBP12.6 plays an important role in hypoxia- and neurotransmitter-induced Ca2+ and contractile responses by regulating the activity of RyRs in PASMCs.
FKBP12., 6, Calcium release, Contraction, Hypoxia, Pulmonary artery myocyte
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