Mechanisms of Gap Junction Regulation

间隙连接调节机制

• 批准号: 10654022
• 负责人: PAUL L SORGEN
• 金额: $ 49.8万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654022
• 关键词: Acute; Affect; Arrhythmia; Basic Science; Binding; Cardiac; Cells; Characteristics; Chronic; Clinical; Connexin 43; Connexins; Coupling; Cytoplasm; Data; Development; Disease; Distal; F-Actin; Gap Junctions; Growth; Growth Factor; Heart; Heart Diseases; Heart failure; Hypertrophy; In Vitro; Infarction; Integral Membrane Protein; Intercalated disc; Ion Exchange; Ischemia; Knowledge; Lateral; Left ventricular structure; Link; Mediating; Membrane; Morphology; Muscle Cells; Myocardial Infarction; Myocardial dysfunction; Myocardium; Pathologic; Pathology; Pathway interactions; Permeability; Phosphorylation; Phosphotransferases; Process; Property; Proteins; Regulation; Research; Role; SRC gene; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Therapeutic Intervention; Tubulin; Up-Regulation; Ventricular; Ventricular Arrhythmia; beta Tubulin; cytokine; density; drebrins; effective therapy; experimental study; gap junction channel; heart rhythm; human disease; insight; intercellular communication; interdisciplinary approach; interest; intermolecular interaction; molecular mass; mouse model; novel; prevent; voltage

Abstract: Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular-mass metabolites between adjacent cells. They provide a pathway for propagating and/or amplifying the signal transduction cascades triggered by cytokines, growth factors, and other cell signaling molecules involved in growth regulation and development. Dysfunctional intercellular communication via gap junctions has been implicated in causing many human diseases. The objective of this project is to use a multi-disciplinary approach to identify the key intrinsic regulatory mechanisms that are responsible for Cx43 and Cx45 function. The central hypothesis is that unique intermolecular interactions within the divergent CT domain of connexins affect gap junction regulation. More specifically, we hypothesize that after myocardial infarction, differential regulation of Cx43 and Cx45 involves specific phosphorylations and protein interactions of their CT domain. The significance of this proposal is that discovery of how interactions mediated by the CT domain can be modulated would open the door to strategies to ameliorate pathological effects of altered connexin regulation in the failing heart. The following Specific Aims are proposed to investigate this concept: 1) What drives Cx43 away from gap junctions/intercalated discs in vitro and in a murine model of myocardial infarction? and 2) What promotes Cx45 gap junction/intercalated disc localization and is Cx45 expression in left ventricle hypertrophy after myocardial infarction an arrhythmogenic substrate? Upon completion of this project, we expect to describe novel mechanisms by which phosphorylation and protein partners regulate Cx43 and Cx45 function and strategies by which the pathological effects of Pyk2, Src, and Cx45 upregulation in failing hearts may be lessened.

摘要： 缝隙连接是一种完整的膜蛋白，它能使细胞内的离子直接交换， 相邻细胞之间的分子量代谢物。它们提供了一条传播和/或扩增 由细胞因子、生长因子和其他细胞信号分子触发的信号转导级联 参与生长调节和发育。通过间隙连接的细胞间通讯功能障碍 与许多人类疾病有关。该项目的目标是使用多学科 方法来确定负责Cx43和Cx45功能的关键内在调节机制。 中心假设是，独特的分子间相互作用内的分歧CT域的连接蛋白 影响间隙连接调节。更具体地说，我们假设心肌梗死后， Cx43和Cx45的调节涉及其CT结构域的特异性磷酸化和蛋白质相互作用。的 该建议意义在于发现了如何调节由CT结构域介导的相互作用 将打开大门的战略，以改善病理影响的改变连接蛋白调节的失败， 心本文提出了以下具体的研究目标：1）是什么驱使Cx43远离gap 连接/闰盘在体外和小鼠模型的心肌梗死？2）什么促进了Cx45 心肌梗死后左室肥厚心肌间隙连接/闰盘定位及Cx45表达的研究 梗死是一种致瘤基质？在这个项目完成后，我们希望描述小说 磷酸化和蛋白质伴侣调节Cx43和Cx45功能的机制和策略， 其可以减轻衰竭心脏中Pyk 2、Src和Cx45上调的病理作用。

项目成果

An Escherichia coli strain for expression of the connexin45 carboxyl terminus attached to the 4th transmembrane domain.

• DOI: 10.3389/fphar.2013.00106
• 发表时间: 2013
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Kopanic JL;Al-Mugotir M;Zach S;Das S;Grosely R;Sorgen PL
• 通讯作者: Sorgen PL

A model for the role of EHD1-containing membrane tubules in endocytic recycling.

含 EHD1 的膜管在内吞再循环中的作用模型。

• DOI: 10.4161/cib.2.5.9157
• 发表时间: 2009
• 期刊: Communicative & integrative biology
• 作者: Sharma,Mahak;Jovic,Marko;Kieken,Fabien;Naslavsky,Naava;Sorgen,Paul;Caplan,Steve
• 通讯作者: Caplan,Steve

Chemical shift assignments of the connexin45 carboxyl terminal domain: monomer and dimer conformations.

• DOI: 10.1007/s12104-012-9431-9
• 发表时间: 2013-10
• 期刊: Biomolecular NMR assignments
• 影响因子: 0.9
• 作者: Kopanic JL;Sorgen PL
• 通讯作者: Sorgen PL

Calmodulin Directly Interacts with the Cx43 Carboxyl-Terminus and Cytoplasmic Loop Containing Three ODDD-Linked Mutants (M147T, R148Q, and T154A) that Retain α-Helical Structure, but Exhibit Loss-of-Function and Cellular Trafficking Defects.

• DOI: 10.3390/biom10101452
• 发表时间: 2020-10-17
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Zheng L;Chenavas S;Kieken F;Trease A;Brownell S;Anbanandam A;Sorgen PL;Spagnol G
• 通讯作者: Spagnol G

Regulation of Cx43 Gap Junction Intercellular Communication by Bruton's Tyrosine Kinase and Interleukin-2-Inducible T-Cell Kinase.

Bruton的酪氨酸激酶和白细胞介素-2诱导的T细胞激酶对CX43 GAP连接间互通的调节。

• DOI: 10.3390/biom13040660
• 发表时间: 2023-04-08
• 期刊: Biomolecules
• 影响因子: 5.5