39 results on '"Jieting Luo"'
Search Results
2. What Do You Care About: Inferring Values from Emotions.
- Author
-
Jieting Luo, Mehdi Dastani, Thomas Studer, and Beishui Liao
- Published
- 2023
- Full Text
- View/download PDF
3. Value-Based Practical Reasoning: Modal Logic + Argumentation.
- Author
-
Jieting Luo, Beishui Liao, and Dov M. Gabbay
- Published
- 2022
- Full Text
- View/download PDF
4. Modeling Affective Reaction in Multi-agent Systems.
- Author
-
Jieting Luo and Mehdi Dastani
- Published
- 2022
- Full Text
- View/download PDF
5. Distinct functional and molecular profiles between physiological and pathological atrial enlargement offer potential new therapeutic opportunities for atrial fibrillation.
- Author
-
Yi Ching Chen, Wijekoon, Seka, Matsumoto, Aya, Jieting Luo, Kiriazis, Helen, Masterman, Emma, Yildiz, Gunes, Cross, Jonathon, Parslow, Adam C., Chooi, Roger, Sadoshima, Junichi, Greening, David W., Weeks, Kate L., and McMullen, Julie R.
- Subjects
INSULIN-like growth factor receptors ,SOMATOMEDIN C ,HEART failure ,ATRIAL fibrillation ,HEART fibrosis - Abstract
Atrial fibrillation (AF) remains challenging to prevent and treat. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to AF. Atrial enlargement in response to physiological stimuli such as exercise is typically benign and reversible. Understanding the differences in atrial function and molecular profile underpinning pathological and physiological atrial remodelling will be critical for identifying new strategies for AF. The discovery of molecular mechanisms responsible for pathological and physiological ventricular hypertrophy has uncovered new drug targets for heart failure. Studies in the atria have been limited in comparison. Here, we characterised mouse atria from (1) a pathological model (cardiomyocyte-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and (2) a physiological model (cardiomyocyte-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Both models presented with an increase in atrial mass, but displayed distinct functional, cellular, histological and molecular phenotypes. Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Atrial proteomics identified protein networks related to cardiac contractility, sarcomere assembly, metabolism, mitochondria, and extracellular matrix which were differentially regulated in the models; many co-identified in atrial proteomics data sets from human AF. In summary, physiological and pathological atrial enlargement are associated with distinct features, and the proteomic dataset provides a resource to study potential new regulators of atrial biology and function, drug targets and biomarkers for AF. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. Applying Abstract Argumentation to Normal-Form Games.
- Author
-
You Cheng, Beishui Liao, and Jieting Luo
- Published
- 2021
- Full Text
- View/download PDF
7. A Formal Framework for Reasoning about Opportunistic Propensity in Multi-agent Systems.
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Max Knobbout
- Published
- 2020
- Full Text
- View/download PDF
8. Eliminating Opportunism using an Epistemic Mechanism.
- Author
-
Jieting Luo, Max Knobbout, and John-Jules Ch. Meyer
- Published
- 2018
9. Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice
- Author
-
Yow Keat Tham, Bianca C. Bernardo, Bethany Claridge, Gunes S. Yildiz, Liesel Min-Linn Woon, Simon Bond, Haoyun Fang, Jenny Y. Y. Ooi, Aya Matsumoto, Jieting Luo, Celeste M. K. Tai, Claudia A. Harmawan, Helen Kiriazis, Daniel G. Donner, Natalie A. Mellett, E. Dale Abel, Sohaib A. Khan, David P. De Souza, Sheik Nadeem Elahee Doomun, Kevin Liu, Ruidong Xiang, Manika Singh, Michael Inouye, Peter J. Meikle, Kate L. Weeks, Brian G. Drew, David W. Greening, and Julie R. McMullen
- Published
- 2023
10. Reasoning About Opportunistic Propensity in Multi-agent Systems.
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Max Knobbout
- Published
- 2017
- Full Text
- View/download PDF
11. Monitoring Opportunism in Multi-agent Systems.
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Max Knobbout
- Published
- 2016
- Full Text
- View/download PDF
12. Towards a Framework for Predicting Opportunism in Multi-agent Systems.
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Max Knobbout
- Published
- 2017
13. Towards A Formal Model of Opportunism Based on Situation Calculus.
- Author
-
Jieting Luo, Frank Dignum, and John-Jules Ch. Meyer
- Published
- 2015
- Full Text
- View/download PDF
14. On Formalizing Opportunism Based on Situation Calculus.
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Frank Dignum
- Published
- 2015
- Full Text
- View/download PDF
15. Learning sufficient scene representation for unsupervised cross-modal retrieval
- Author
-
Bicheng Wu, Yan Wo, Jieting Luo, and Guoqiang Han
- Subjects
Modality (human–computer interaction) ,Similarity (geometry) ,Computer science ,business.industry ,Cognitive Neuroscience ,Representation (systemics) ,Pattern recognition ,Mixture model ,Computer Science Applications ,Statistical manifold ,Artificial Intelligence ,Binary code ,Artificial intelligence ,Focus (optics) ,Quantization (image processing) ,business - Abstract
In this paper, a novel unsupervised Cross-Modal retrieval method via Sufficient Scene Representation (CMSSR) is proposed. Distinguished from the existing methods which mainly focus on simultaneously preserving the mutually-constrained intra- and inter-modal similarity relation, CMSSR considers data of different modalities as the descriptions of a scene from different views and accordingly integrates information of different modalities to learn a complete common representation containing sufficient information of the corresponding scene. To obtain such common representation, Gaussian Mixture Model (GMM) is firstly utilized to generate statistic representation of each uni-modal data, while the uni-modal spaces are accordingly abstracted as uni-modal statistical manifolds. In addition, the common space is assumed to be a high-dimensional statistical manifold with different uni-modal statistical manifolds as its sub-manifolds. In order to generate sufficient scene representation from uni-modal data, a representation completion strategy based on logistic regression is proposed to effectively complete the missing representation of another modality. Then, the similarity between different multi-modal data can be more accurately reflected by the distance metric in common statistical manifold. Based on the distance metric in common statistical manifold, Iterative Quantization is utilized to further generate binary code for fast cross-modal retrieval. Extensive experiments on three standard benchmark datasets fully demonstrate the superiority of CMSSR compared with several state-of-the-art methods.
- Published
- 2021
16. Phosphoproteomic profiling of isolated murine cardiomyocytes reveals a role for protein phosphatase 2A (PP2A) regulatory subunit B55α as a regulator of β-adrenergic receptor signaling in the heart
- Author
-
Nicola M. Sergienko, Helen Kiriazis, Daniel Donner, Aya Matsumoto, Jieting Luo, Jeffrey Molendijk, Ben L. Parker, Julie McMullen, and Kate Weeks
- Subjects
Cardiology and Cardiovascular Medicine ,Molecular Biology - Published
- 2022
17. Towards a Framework for Detecting Opportunism in Multi-Agent Systems.
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Max Knobbout
- Published
- 2016
- Full Text
- View/download PDF
18. Applying Abstract Argumentation to Normal-Form Games
- Author
-
Jieting Luo, Beishui Liao, and You Cheng
- Subjects
Computer Science::Computer Science and Game Theory ,Computer science ,ComputingMilieux_PERSONALCOMPUTING ,Mathematical economics ,Argumentation framework ,Game theory ,Argumentation theory - Abstract
Game theory is the most common approach to studying strategic interactions between agents, but it provides little explanation for game-theoretical solution concepts. In this paper, we use a game-based argumentation framework to solve normal-form games. The result is that solution concepts in game theory can be interpreted by extensions of a game-based argumentation framework. We can use our framework to solve normal-form games, providing explanation for solution concepts.
- Published
- 2021
19. Engineering Multi-Agent Systems : 11th International Workshop, EMAS 2023, London, UK, May 29–30, 2023, Revised Selected Papers
- Author
-
Andrei Ciortea, Mehdi Dastani, Jieting Luo, Andrei Ciortea, Mehdi Dastani, and Jieting Luo
- Subjects
- Artificial intelligence, Computer engineering, Computer networks, Application software, Computer science
- Abstract
This book constitutes revised selected papers from the 11th International Workshop on Engineering Multi-Agent Systems, EMAS 2023, which was held in London, UK, during May 29–30, 2023.The 11 full papers and 7 short papers included in this volume were carefully reviewed and selected from a total of 25 submissions. They were organized in topical sections as follows: agent-oriented software engineering; agents and microservices; strategy, reasoning, and planning; engineering domains and applications; agents in hypermedia environments; frameworks, tooling, and devops.
- Published
- 2023
20. Logic and Argumentation : 5th International Conference, CLAR 2023, Hangzhou, China, September 10-12, 2023, Proceedings
- Author
-
Andreas Herzig, Jieting Luo, Pere Pardo, Andreas Herzig, Jieting Luo, and Pere Pardo
- Subjects
- Artificial intelligence, Computer programming, Compilers (Computer programs), Algorithms, Computer science, Machine theory
- Abstract
This book constitutes the refereed proceedings of the 5th International Conference on Logic and Argumentation, CLAR 2023, held in Hangzhou, China, during September 10-12, 2023. The 11 full papers, one short paper and one invited paper presented in this book were carefully reviewed and selected from 20 submissions. The papers focus on topics such as: logic and automated deduction; abstract and structured argumentation; dialogues, games and practical reasoning; and quantitative argumentation.
- Published
- 2023
21. Proteome characterisation of extracellular vesicles isolated from heart
- Author
-
Aya Matsumoto, Haoyun Fang, Bethany Claridge, Alin Rai, Jieting Luo, David W. Greening, and Julie R. McMullen
- Subjects
Proteomics ,Differential centrifugation ,0303 health sciences ,Proteome ,TNNT2 ,Chemistry ,030302 biochemistry & molecular biology ,Endothelial Cells ,Biochemistry ,Cell biology ,Extracellular Vesicles ,Mice ,03 medical and health sciences ,Proteostasis ,Animals ,TSG101 ,Glycolysis ,Molecular Biology ,Biomarkers ,Intracellular ,030304 developmental biology - Abstract
Cardiac intercellular communication is critical for heart function and often dysregulated in cardiovascular diseases. While cardiac extracellular vesicles (cEVs) are emerging mediators of signalling, their isolation remains a technical challenge hindering our understanding of cEV protein composition. Here, we utilised Langendorff-collagenase-based enzymatic perfusion and differential centrifugation to isolate cEVs from mouse heart (yield 3-6 μg/heart). cEVs are ∼200 nm, express classical EV markers (Cd63/81/9+ , Tsg101+ , Pdcd6ip/Alix+ ), and are depleted of blood (Alb/Fga/Hba) and cardiac damage markers (Mb, Tnnt2, Ldhb). Comparison with mechanically-derived EVs revealed greater detection of EV markers and decreased cardiac damage contaminants. Mass spectrometry-based proteomic profiling revealed 1721 proteins in cEVs, implicated in proteasomal and autophagic proteostasis, glycolysis, and fatty acid metabolism; essential functions often disrupted in cardiac pathologies. There was striking enrichment of 942 proteins in cEVs compared to mouse heart tissue - implicated in EV biogenesis, antioxidant activity, and lipid transport, suggesting active cargo selection and specialised function. Interestingly, cEVs contain marker proteins for cardiomyocytes, cardiac progenitors, B-cells, T-cells, macrophages, smooth muscle cells, endothelial cells, and cardiac fibroblasts, suggesting diverse cellular origin. We present a method of cEV isolation and provide insight into potential functions, enabling future studies into EV roles in cardiac physiology and disease.
- Published
- 2021
22. A robust ant colony optimization for continuous functions
- Author
-
Zhiming Chen, Shaorui Zhou, and Jieting Luo
- Subjects
Continuous optimization ,0209 industrial biotechnology ,Mathematical optimization ,Computer science ,Ant colony optimization algorithms ,General Engineering ,Intelligent decision support system ,02 engineering and technology ,Computer Science Applications ,Domain (software engineering) ,020901 industrial engineering & automation ,Artificial Intelligence ,Robustness (computer science) ,0202 electrical engineering, electronic engineering, information engineering ,Pheromone ,020201 artificial intelligence & image processing ,Metaheuristic - Abstract
The robust ant colony algorithm for continuous optimization is very simple to use.It doesn't make any major conceptual change to ant colony optimization's structure.It uses a broad-range search which enables ants to search in a new domain.It is robust to initial domain's properties such as length, symmetry and border.It can find the correct result in given domains without optimal solution. Ant colony optimization (ACO) for continuous functions has been widely applied in recent years in different areas of expert and intelligent systems, such as steganography in medical systems, modelling signal strength distribution in communication systems, and water resources management systems. For these problems that have been addressed previously, the optimal solutions were known a priori and contained in the pre-specified initial domains. However, for practical problems in expert and intelligent systems, the optimal solutions are often not known beforehand. In this paper, we propose a robust ant colony optimization for continuous functions (RACO), which is robust to domains of variables. RACO applies self-adaptive approaches in terms of domain adjustment, pheromone increment, domain division, and ant size without any major conceptual change to ACO's framework. These new characteristics make the search of ants not limited to the given initial domain, but extended to a completely different domain. In the case of initial domains without the optimal solution, RACO can still obtain the correct result no matter how the initial domains vary. In the case of initial domains with the optimal solution, we also show that RACO is a competitive algorithm. With the assistance of RACO, there is no need to estimate proper initial domains for practical continuous optimization problems in expert and intelligent systems.
- Published
- 2017
23. Phospholipase Cβ1b directly binds the SH3 domain of Shank3 for targeting and activation in cardiomyocytes
- Author
-
Elizabeth A. Woodcock, Jieting Luo, and David R. Grubb
- Subjects
Scaffold protein ,Binding Sites ,Sarcolemma ,Alternative splicing ,Phospholipase C beta ,Biophysics ,DHR1 domain ,Nerve Tissue Proteins ,Cell Biology ,Biology ,Phospholipase ,Biochemistry ,Molecular biology ,SH3 domain ,Enzyme Activation ,src Homology Domains ,Signalling ,Animals ,Myocytes, Cardiac ,Molecular Biology ,Protein ligand - Abstract
Phospholipase Cβ1b (PLCβ1b) is an atypical splice variant of PLCβ1 that has a C-terminal proline-rich sequence instead of the PDZ-interacting motif common to other PLCβ subtypes. PLCβ1b targets to the cardiomyocyte sarcolemma through an undefined association with the scaffolding protein Shank3. The C-terminal splice variant specific sequence of PLCβ1b bound to deletion mutants of Shank3 that included the SH3 domain, but not to constructs lacking this domain. Mutating proline residues in the extreme C-terminal region of PLCβ1b prevented the interaction between PLCβ1b and Shank3 resulting in reduced sarcolemmal localization and downstream signalling responses. We conclude that PLCβ1b activation and downstream signalling require the association of a previously unidentified C-terminal proline-rich motif with the SH3 domain of Shank3. PLCβ1b is the first confirmed protein ligand for the SH3 domain of Shank3.
- Published
- 2015
24. Monitoring Opportunism in Multi-agent Systems
- Author
-
Jieting Luo, John-Jules Ch. Meyer, and Max Knobbout
- Subjects
Logical framework ,Risk analysis (engineering) ,Computer science ,Multi-agent system ,Opportunism ,Norm (social) ,Enforcement - Abstract
Opportunism is a behavior that causes norm violation and promotes agents’ own value. In the context of multi-agent systems, it is important to constrain such a selfish behavior through setting enforcement norms. Because opportunistic behavior cannot be observed directly, there has to be a monitoring mechanism that can detect the performance of opportunistic behavior in the system. This paper provides a logical framework based on the specification of actions to specify monitoring approaches for opportunism. We investigate how to evaluate agents’ actions to be opportunistic with respect to different forms of norms when those actions cannot be observed directly, and study how to reduce the monitoring cost for opportunism.
- Published
- 2017
25. Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P3 and IP3-receptors
- Author
-
Jieting Luo, Albert Wong, David R. Grubb, Nicola Cooley, and Elizabeth A. Woodcock
- Subjects
Boron Compounds ,Autophagosome ,Heart Ventricles ,Cellular differentiation ,Nerve Tissue Proteins ,FOXO1 ,Inositol 1,4,5-Trisphosphate ,Biology ,Cytoplasmic Granules ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Phagosomes ,Sequestosome-1 Protein ,Autophagy ,Animals ,Inositol 1,4,5-Trisphosphate Receptors ,Myocytes, Cardiac ,Inositol ,Receptor ,Molecular Biology ,Cells, Cultured ,Heat-Shock Proteins ,Binding Sites ,Phosphatidylethanolamines ,Wild type ,Bafilomycin ,Forkhead Transcription Factors ,Protein Structure, Tertiary ,Rats ,Cell biology ,chemistry ,Proteolysis ,Beclin-1 ,Apoptosis Regulatory Proteins ,Lysosomes ,Cardiology and Cardiovascular Medicine ,Microtubule-Associated Proteins ,Protein Binding ,Signal Transduction - Abstract
Autophagy is a process that removes damaged proteins and organelles and is of particular importance in terminally differentiated cells such as cardiomyocytes, where it has primarily a protective role. We investigated the involvement of inositol(1,4,5)trisphosphate (Ins(1,4,5)P(3)) and its receptors in autophagic responses in neonatal rat ventricular myocytes (NRVM). Treatment with the IP(3)-receptor (IP(3)-R) antagonist 2-aminoethoxydiphenyl borate (2-APB) at 5 or 20 μmol/L resulted in an increase in autophagosome content, defined as puncta labeled by antibody to microtubule associated light chain 3 (LC3). 2-APB also increased autophagic flux, indicated by heightened LC3II accumulation, which was further enhanced by bafilomycin (10nmol/L). Expression of Ins(1,4,5)P(3) 5-phosphatase (IP(3)-5-Pase) to deplete Ins(1,4,5)P(3) also increased LC3-labeled puncta and LC3II content, suggesting that Ins(1,4,5)P(3) inhibits autophagy. The IP(3)-R can act as an inhibitory scaffold sequestering the autophagic effector, beclin-1 to its ligand binding domain (LBD). Expression of GFP-IP(3)-R-LBD inhibited autophagic signaling and furthermore, beclin-1 co-immunoprecipitated with the IP(3)-R-LBD. A mutant GFP-IP(3)-R-LBD with reduced ability to bind Ins(1,4,5)P(3) bound beclin-1 and inhibited autophagy similarly to the wild type sequence. These data provide evidence that Ins(1,4,5)P(3) and IP(3)-R act as inhibitors of autophagic responses in cardiomyocytes. By suppressing autophagy, IP(3)-R may contribute to cardiac pathology.
- Published
- 2013
26. Scaffolding protein Homer 1c mediates hypertrophic responses downstream of Gq in cardiomyocytes
- Author
-
David R. Grubb, Elizabeth A. Woodcock, Jieting Luo, and Yen Lin Yu
- Subjects
Scaffold protein ,Cell ,Phospholipase C beta ,Nerve Tissue Proteins ,Cell Enlargement ,In Vitro Techniques ,Phospholipase ,Biochemistry ,Rats, Sprague-Dawley ,Sarcolemma ,Homer Scaffolding Proteins ,Heterotrimeric G protein ,Genetics ,medicine ,Animals ,Myocytes, Cardiac ,Calcium Signaling ,RNA, Messenger ,RNA, Small Interfering ,Receptor ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Base Sequence ,biology ,Chemistry ,Models, Cardiovascular ,Rats ,Cell biology ,medicine.anatomical_structure ,Animals, Newborn ,Gq alpha subunit ,Gene Knockdown Techniques ,Multiprotein Complexes ,biology.protein ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Carrier Proteins ,Intracellular ,Signal Transduction ,Biotechnology - Abstract
Activation of the heterotrimeric G protein, Gq, causes cardiomyocyte hypertrophy in vivo and in cell models. Responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because it localizes at the sarcolemma by binding to Shank3, a high-molecular-weight (MW) scaffolding protein. Shank3 can bind to the Homer family of low-MW scaffolding proteins that fine tune Ca(2+) signaling by facilitating crosstalk between Ca(2+) channels at the cell surface with those on intracellular Ca(2+) stores. Activation of α(1)-adrenergic receptors, expression of constitutively active Gαq (GαqQL), or PLCβ1b initiated cardiomyocyte hypertrophy and increased Homer 1c mRNA expression, by 1.6 ± 0.18-, 1.9 ± 0.17-, and 1.5 ± 0.07-fold, respectively (means ± se, 6 independent experiments, P0.05). Expression of Homer 1c induced an increase in cardiomyocyte area from 853 ± 27 to 1146 ± 31 μm(2) (P0.05); furthermore, expression of dominant-negative Homer (Homer 1a) reversed the increase in cell size caused by α(1)-adrenergic agonist or PLCβ1b treatment (1503±48 to 996±28 and 1626±48 to 828±31 μm(2), respectively, P0.05). Homer proteins were localized near the sarcolemma, associated with Shank3 and phospholipase Cβ1b. We conclude that Gq-mediated hypertrophy involves activation of PLCβ1b scaffolded onto a Shank3/Homer complex. Signaling downstream of Homer 1c is necessary and sufficient for Gq-initiated hypertrophy.
- Published
- 2011
27. Phospholipase Cβlb associates with a Shank3 complex at the cardiac sarcolemma
- Author
-
Peter Iliades, Jieting Luo, Elizabeth A. Woodcock, David R. Grubb, Nicola Cooley, Theresa M. Filtz, and Yen Lin Yu
- Subjects
Scaffold protein ,Sarcolemma ,Chemistry ,HEK 293 cells ,Signal transducing adaptor protein ,Phospholipase ,Biochemistry ,SH3 domain ,Cell biology ,Heterotrimeric G protein ,Genetics ,Myocyte ,Molecular Biology ,Biotechnology - Abstract
Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell models. Our previous studies have shown that responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because only this PLCβ subtype localizes at the cardiac sarcolemma. In the current study, we investigated the proteins involved in targeting PLCβ1b to the sarcolemma in neonatal rat cardiomyocytes. PLCβ1b, but not PLCβ1a, coimmunoprecipitated with the high-MW scaffolding protein SH3 and ankyrin repeat protein 3 (Shank3), as well as the known Shank3-interacting protein α-fodrin. The 32-aa splice-variant-specific C-terminal tail of PLCβ1b also associated with Shank3 and α-fodrin, indicating that PLCβ1b binds via the C-terminal sequence. Shank3 colocalized with PLCβ1b at the sarcolemma, and both proteins were enriched in the light membrane fractions. Knockdown of Shank3 using siRNA reduced PLC activation and downstream hypertrophic responses, demonstrating the importance of sarcolemmal localization for PLC signaling. These data indicate that PLCβ1b associates with a Shank3 complex at the cardiac sarcolemma via its splice-variant-specific C-terminal tail. Sarcolemmmal localization is central to PLC activation and subsequent downstream signaling following Gq-coupled receptor activation.
- Published
- 2010
28. Ins(1,4,5)P3 regulates phospholipase Cβ1 expression in cardiomyocytes
- Author
-
Theresa M. Filtz, Oliver Vasilevski, Jieting Luo, Elizabeth A. Woodcock, Tiffany J. McLeod-Dryden, Sundy Yang, Divya Karna, David R. Grubb, and Ju Chen
- Subjects
Heart Ventricles ,Phospholipase C beta ,Stimulation ,Inositol 1,4,5-Trisphosphate ,Biology ,Phospholipase ,Gene Expression Regulation, Enzymologic ,Adenoviridae ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Animals ,Humans ,Myocytes, Cardiac ,Inositol ,Phosphatidylinositol ,Receptor ,Molecular Biology ,Mice, Knockout ,Muscle Cells ,Phospholipase C ,Reverse Transcriptase Polymerase Chain Reaction ,Molecular biology ,Rats ,Pleckstrin homology domain ,Animals, Newborn ,Biochemistry ,chemistry ,Second messenger system ,Cardiology and Cardiovascular Medicine - Abstract
The functional significance of the Ca2+-releasing second messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P(3), IP(3)) in the heart has been controversial. Ins(1,4,5)P(3) is generated from the precursor lipid phosphatidylinositol(4,5)bisphosphate (PIP(2)) along with sn-1,2-diacylglycerol, and both of these are important cardiac effectors. Therefore, to evaluate the functional importance of Ins(1,4,5)P(3) in cardiomyocytes (NRVM), we overexpressed IP(3) 5-phosphatase to increase degradation. Overexpression of IP(3) 5-phosphatase reduced Ins(1,4,5)P(3) responses to alpha(1)-adrenergic receptor agonists acutely, but with longer stimulation, caused an overall increase in phospholipase C (PLC) activity, associated with a selective increase in expression of PLCbeta1, that served to normalise Ins(1,4,5)P(3) content. Similar increases in PLC activity and PLCbeta1 expression were observed when Ins(1,4,5)P(3) was sequestered onto the PH domain of PLCdelta1, a high affinity selective Ins(1,4,5)P(3)-binding motif. These findings suggested that the available level of Ins(1,4,5)P(3) selectively regulates the expression of PLCbeta1. Cardiac responses to Ins(1,4,5)P(3) are mediated by type 2 IP(3)-receptors. Hearts from IP(3)-receptor (type 2) knock-out mice showed heightened PLCbeta1 expression. We conclude that Ins(1,4,5)P(3) and IP(3)-receptor (type 2) regulate PLCbeta1 and thereby maintain levels of Ins(1,4,5)P(3). This implies some functional significance for Ins(1,4,5)P(3) in the heart.
- Published
- 2008
29. The atypical 'b' splice variant of phospholipase Cβ1 promotes cardiac contractile dysfunction
- Author
-
H. Qian, Xiao-Jun Du, Xiao-Ming Gao, Jieting Luo, Paul Gregorevic, Helen Kiriazis, Elizabeth A. Woodcock, Yi Ma, Bryony Crook, and David R. Grubb
- Subjects
medicine.medical_specialty ,SERCA ,Phospholipase C beta ,Phospholipase ,Biology ,Contractility ,Internal medicine ,medicine ,Animals ,Phosphorylation ,Molecular Biology ,Protein Kinase Inhibitors ,Protein kinase C ,TRPC ,Protein Kinase C ,Ultrasonography ,Sarcolemma ,Myocardium ,Calcium-Binding Proteins ,Hemodynamics ,Heart ,Dependovirus ,Fibrosis ,Myocardial Contraction ,Phospholamban ,Mice, Inbred C57BL ,Alternative Splicing ,Endocrinology ,Administration, Intravenous ,Hypertrophy, Left Ventricular ,Signal transduction ,Cardiology and Cardiovascular Medicine - Abstract
The activity of the early signaling enzyme, phospholipase Cβ1b (PLCβ1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLCβ1b activity to cardiac pathology. PLCβ1b, the alternative splice variant, PLCβ1a, and a blank virus were expressed in mouse hearts using adeno-associated viral vectors (rAAV6-FLAG-PLCβ1b, rAAV6-FLAG-PLCβ1a, or rAAV6-blank) delivered intravenously (IV). Following viral delivery, FLAG-PLCβ1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLCβ1b expression caused a rapid loss of contractility, 4–6 weeks, that was fully reversed, within 5 days, by inhibition of protein kinase Cα (PKCα). PLCβ1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLCβ1b, but not PLCβ1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca2 + stores of the sarcoplasmic reticulum. We conclude that heightened PLCβ1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCβ1b is a cardiac-specific signaling system, and thus provides a potential therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium.
- Published
- 2015
30. Towards A Formal Model of Opportunism Based on Situation Calculus
- Author
-
John-Jules Ch. Meyer, Frank Dignum, and Jieting Luo
- Subjects
Microeconomics ,Computer science ,Opportunism ,Opposition (politics) ,Situation calculus ,Value (mathematics) - Abstract
Opportunism is a social behavior that achieves own gains at the expense of others. In this study, we propose a formal model of opportunism, which consists of the properties knowledge asymmetry, value opposition and intention, based on situation calculus.
- Published
- 2015
31. The phosphatidylinositol(4,5)bisphosphate-binding sequence of transient receptor potential channel canonical 4α is critical for its contribution to cardiomyocyte hypertrophy
- Author
-
Nicola Cooley, Jieting Luo, Elizabeth A. Woodcock, and David R. Grubb
- Subjects
Male ,Phosphatidylinositol 4,5-Diphosphate ,Phospholipase C beta ,Cardiomegaly ,Nerve Tissue Proteins ,Biology ,TRPC4 ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Transient receptor potential channel ,Sarcolemma ,Animals ,Protein Isoforms ,Myocytes, Cardiac ,Phosphatidylinositol ,Receptor ,TRPC ,TRPC Cation Channels ,Pharmacology ,Binding Sites ,Phospholipase C ,Molecular biology ,Rats ,Protein Transport ,Phosphatidylinositol 4,5-bisphosphate ,chemistry ,Mutation ,Molecular Medicine ,Female ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Atrial Natriuretic Factor ,Protein Binding - Abstract
Cardiomyocyte hypertrophy requires a source of Ca(2+) distinct from the Ca(2+) that regulates contraction. The canonical transient receptor potential channel (TrpC) family, a family of cation channels regulated by activation of phospholipase C (PLC), has been implicated in this response. Cardiomyocyte hypertrophy downstream of Gq-coupled receptors is mediated specifically by PLCβ1b that is scaffolded onto a SH3 and ankyrin repeat protein 3 (Shank3) complex at the sarcolemma. TrpC4 exists as two splice variants (TrpC4α and TrpC4β) that differ only in an 84-residue sequence that binds to phosphatidylinositol(4,5)bisphosphate (PIP2), the substrate of PLCβ1b. In neonatal rat cardiomyocytes, TrpC4α, but not TrpC4β, coimmunoprecipitated with both PLCβ1b and Shank3. Heightened PLCβ1b expression caused TrpC4α, but not TrpC4β, translocation to the sarcolemma, where it colocalized with PLCβ1b. When overexpressed in cardiomyocytes, TrpC4α, but not TrpC4β, increased cell area (893 ± 18 to 1497 ± 29 mm(2), P0.01) and marker gene expression (atrial natriuretic peptide increased by 409 ± 32%, and modulatory calcineurin inhibitory protein 1 by 315 ± 28%, P0.01). Dominant-negative TrpC4 reduced hypertrophy initiated by PLCβ1b, or PLCβ1b-coupled receptor activation, by 72 ± 8% and 39 ± 5 %, respectively. We conclude that TrpC4α is selectively involved in mechanisms downstream of PLCβ1b culminating in cardiomyocyte hypertrophy, and that the hypertrophic response is dependent on the TrpC4α splice variant-specific sequence that binds to PIP2.
- Published
- 2014
32. Abstract 33: Contractile Dysfunction In The Mouse Heart Caused By Phospholipase C beta1b Mediated Activation Of Protein Kinase Calpha
- Author
-
David R Grubb, Yi Ma, Jieting Luo, Bryony Crook, Nicola Cooley, Helen Kiriazis, Hong Wei Qian, Paul Gregorevic, Xiao-Ming Gao, Xiao-Jun Du, and Elizabeth A Woodcock
- Subjects
Physiology ,Cardiology and Cardiovascular Medicine - Abstract
The activity of the early signaling enzyme, phospholipase Cβ1b (PLCβ1b), is elevated in diseased myocardium and activity increases with disease progression. PLCβ1b and the alternative splice variant, PLCβ1a, were expressed in mouse hearts using adeno-associated viral constructs (rAAV6-FLAG-PLCβ1b, rAAV6-FLAG- PLCβ1a) delivered intravenously. Functional responses were assessed in vivo and confirmatory mechanistic studies were conducted in neonatal rat ventricular myocytes (NRVM). FLAG-PLCβ1b was expressed in all of the chambers of the mouse heart, but was highest in left ventricle, where expression was observed in >90% of the cells and was localized to the sarcolemma and T-tubules. Heightened PLCβ1b expression caused a rapid loss of contractility and down-regulation of Phospholamban expression. The loss of contractility induced by PLCβ1b was reversed by inhibition of protein kinase Cα (PKCα). PLCβ1a did not affect contractile function or phospholamban expression. Mechanistic analysis performed in neonatal rat cardiomyocytes confirmed PLCβ1b increased the membrane association of PKCα as well as downstream dephosphorylation of phospholamban and depletion of the Ca2+ stores of the sarcoplasmic reticulum, both of which were mediated by PKCα. Trans-aortic constriction (TAC) resulted in progressive hypertrophy together with reduced contractility in PLCβ1a expressing mice. In PLCβ1b-expressing mice, TAC induced a similar hypertrophic response, but did not cause further contractile depression above that due to PLCβ1b expression alone, suggesting that PLCβ1b is responsible for lowering contractility in response to pressure overload. We conclude that heightened PLCβ1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCβ1b is a cardiac-specific signaling system, and thus provides an ideal therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium.
- Published
- 2014
33. Abstract P225: Possible Involvement of Homer-1b/c in Gq-Mediated Hypertrophy in Cardiomyocytes
- Author
-
David R Grubb, Jieting Luo, Peter Iliades, and Elizabeth A Woodcock
- Subjects
Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Receptor activation of Gq causes hypertrophy in cardiomyocytes, via the activation of phospholipase Cβ 1b (PLCβ1b). PLCβ1b, localizes to the cardiac sarcolemma through an interaction with the multi-domain scaffolding molecule Shank-3 (SH3 and multiple ankyrin repeat domains protein 3; Grubb et al., 2011), which is required for PLC activation and for hypertrophic responses. In the CNS, Shank-3 forms higher order oligomeric complexes with three isoforms of Homer protein homolog 1 (Homer-1), Homer-1a, Homer-1b and Homer-1c. Homer-1b and Homer-1c link G-protein coupled receptors, ionotropic receptors, canonical transient receptor potential channel (TrpC) and intracellular calcium store regulators into a signaling complex. Homer-1a acts as a natural dominant negative, in dynamic competition with Homer-1b and Homer-1c. Neonatal rat ventricular myocytes (NRVM) infected with adenovirus expressing either Gαq(Q209L) (constitutively active Gαq), or its immediate down-stream effector, PLCβ1b, increased Homer-1b/c transcription. Incubation with phenylephrine/propranalol (α 1 -adrenergic agonist, PE/Pro) also increased Homer-1b/c, but not Homer-1a, mRNA. All treatments caused cardiomyocyte hypertrophy. There was no comparable increase in Homer-1b/c mRNA in NRVM expressing PLCβ1a (inactive splice variant) or incubated with fetal calf serum to induce hypertrophy by Gq-independent mechanisms. Homer-1b/c protein induced by PLCβ1b, Gαq or PE/Pro was primarily localized close to the sarcolemma along with Shank3, PLCβ1b and TrpC4. We conclude that Gαq/PLCβ1b-mediated signaling leads to the up-regulation of Homer-1b/c, that co-localizes with a signaling complex close to the sacrolemma. Induction of Homer-1b/c may be critical in facilitating localized Ca 2+ signaling and thereby promoting Gq dependent hypertrophy.
- Published
- 2011
34. Phospholipase Cbeta1b associates with a Shank3 complex at the cardiac sarcolemma
- Author
-
David R, Grubb, Peter, Iliades, Nicola, Cooley, Yen Lin, Yu, Jieting, Luo, Theresa M, Filtz, and Elizabeth A, Woodcock
- Subjects
Cardiotonic Agents ,Myocardium ,Microfilament Proteins ,Phospholipase C beta ,Cardiomegaly ,Nerve Tissue Proteins ,Protein Structure, Tertiary ,Rats ,Rats, Sprague-Dawley ,src Homology Domains ,Alternative Splicing ,Phenylephrine ,HEK293 Cells ,Membrane Microdomains ,Sarcolemma ,Animals ,Humans ,Myocytes, Cardiac ,RNA, Small Interfering ,Carrier Proteins ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Signal Transduction - Abstract
Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell models. Our previous studies have shown that responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because only this PLCβ subtype localizes at the cardiac sarcolemma. In the current study, we investigated the proteins involved in targeting PLCβ1b to the sarcolemma in neonatal rat cardiomyocytes. PLCβ1b, but not PLCβ1a, coimmunoprecipitated with the high-MW scaffolding protein SH3 and ankyrin repeat protein 3 (Shank3), as well as the known Shank3-interacting protein α-fodrin. The 32-aa splice-variant-specific C-terminal tail of PLCβ1b also associated with Shank3 and α-fodrin, indicating that PLCβ1b binds via the C-terminal sequence. Shank3 colocalized with PLCβ1b at the sarcolemma, and both proteins were enriched in the light membrane fractions. Knockdown of Shank3 using siRNA reduced PLC activation and downstream hypertrophic responses, demonstrating the importance of sarcolemmal localization for PLC signaling. These data indicate that PLCβ1b associates with a Shank3 complex at the cardiac sarcolemma via its splice-variant-specific C-terminal tail. Sarcolemmmal localization is central to PLC activation and subsequent downstream signaling following Gq-coupled receptor activation.
- Published
- 2010
35. Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase Cbeta1b
- Author
-
David R. Grubb, Tiffany J. McLeod-Dryden, Jieting Luo, Theresa M. Filtz, and Elizabeth A. Woodcock
- Subjects
Sarcolemma ,Phospholipase C beta ,Cardiomegaly ,Phospholipase ,Biochemistry ,Muscle hypertrophy ,Cell biology ,Rats ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,chemistry ,Heterotrimeric G protein ,Receptors, Adrenergic, alpha-1 ,Phosphoinositide phospholipase C ,Genetics ,Animals ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Inositol ,Myocytes, Cardiac ,Adrenergic alpha-1 Receptor Agonists ,Receptor ,Molecular Biology ,Protein kinase C ,Cells, Cultured ,Biotechnology - Abstract
Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell culture models. Hypertrophic responses induced by pressure or volume overload are exacerbated by increased Gq activity and ameliorated by Gq inhibition. Gq activates phospholipase Cbeta (PLCbeta) subtypes, resulting in generation of the intracellular messengers inositol(1,4,5)tris-phosphate [Ins(1,4,5)P(3)] and sn-1,2-diacylglycerol (DAG), which regulate intracellular Ca(2+) and conventional protein kinase C subtypes, respectively. Gq can also signal independently of PLCbeta, and the involvement of either Ins(1,4,5)P(3) or DAG in cardiomyocyte hypertrophy has not been unequivocally established. Overexpression of one splice variant of PLCbeta1, specifically PLCbeta1b, in neonatal rat cardiomyocytes causes increased cell size, elevated protein/DNA ratio, and heightened expression of the hypertrophy-related marker gene, atrial natriuretic peptide. The other splice variant, PLCbeta1a, had no effect. Expression of a 32-aa C-terminal PLCbeta1b peptide, which competes with PLCbeta1b for sarcolemmal association, prevented PLC activation and eliminated hypertrophic responses initiated by Gq or Gq-coupled alpha(1)-adrenergic receptors. In contrast, a PLCbeta1a C-terminal peptide altered neither PLC activity nor cellular hypertrophy. We conclude that hypertrophic responses initiated by Gq are mediated specifically by PLCbeta1b. Preventing PLCbeta1b association with the sarcolemma may provide a useful therapeutic target to limit hypertrophy.
- Published
- 2009
36. Selective activation of the 'b' splice variant of phospholipase Cbeta1 in chronically dilated human and mouse atria
- Author
-
Chiew Wong, David M. Kaye, Junichi Sadoshima, Xiao-Jun Du, Theresa M. Filtz, Silvana Marasco, Tiffany J. McLeod-Dryden, Julie R. McMullen, Jieting Luo, Anthony M. Dart, Elizabeth A. Woodcock, and David R. Grubb
- Subjects
Cardiomyopathy, Dilated ,medicine.medical_specialty ,Phospholipase C beta ,Biology ,In Vitro Techniques ,chemistry.chemical_compound ,Mice ,Internal medicine ,Atrial Fibrillation ,medicine ,Animals ,Humans ,Atrial Appendage ,Myocytes, Cardiac ,Heart Atria ,Protein kinase A ,Molecular Biology ,Protein kinase C ,Cells, Cultured ,Phospholipase C ,Kinase ,Reverse Transcriptase Polymerase Chain Reaction ,Mitral Valve Insufficiency ,Atrial fibrillation ,Dilated cardiomyopathy ,medicine.disease ,Rats ,Disease Models, Animal ,Endocrinology ,Phosphatidylinositol 4,5-bisphosphate ,chemistry ,Animals, Newborn ,cardiovascular system ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Signal Transduction - Abstract
Atrial fibrillation (AF) is commonly associated with chronic dilatation of the left atrium, both in human disease and animal models. The immediate signaling enzyme phospholipase C (PLC) is activated by mechanical stretch to generate the Ca2+-releasing messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) and sn-1,2-diacylglycerol (DAG), an activator of protein kinase C subtypes. There is also evidence that heightened activity of PLC, caused by the receptor coupling protein Gq, can contribute to atrial remodelling. We examined PLC activation in right and left atrial appendage from patients with mitral valve disease (VHD) and in a mouse model of dilated cardiomyopathy caused by transgenic overexpression of the stress-activated protein kinase, mammalian sterile 20 like kinase 1 (Mst1) (Mst1-TG). PLC activation was heightened 6- to 10-fold in atria from VHD patients compared with right atrial tissue from patients undergoing coronary artery bypass surgery (CABG) and was also heightened in the dilated atria from Mst1-TG. PLC activation in human left atrial appendage and in mouse left atria correlated with left atrial size, implying a relationship between PLC activation and chronic dilatation. Dilated atria from human and mouse showed heightened expression of PLCbeta1b, but not of other PLC subtypes. PLCbeta1b, but not PLCbeta1a, caused apoptosis when overexpressed in neonatal rat cardiomyocytes, suggesting that PLCbeta1b may contribute to chamber dilatation. The activation of PLCbeta1b is a possible therapeutic target to limit atrial remodelling in VHD patients.
- Published
- 2009
37. Scaffolding protein Homer 1c mediates hypertrophic responses downstream of Gq in cardiomyocytes.
- Author
-
Grubb, David R., Jieting Luo, Yen Lin Yu, and Woodcock, Elizabeth A.
- Subjects
- *
G proteins , *MEMBRANE proteins , *HEART cells , *PHOSPHOLIPASES , *ESTERASES - Abstract
Activation of the heterotrimeric G protein, Gq, causes cardiomyocyte hypertrophy in vivo and in cell models. Responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because it localizes at the sarcolemma by binding to Shank3, a high-molecular-weight (MW) scaffolding protein. Shank3 can bind to the Homer family of low-MW scaffolding proteins that fine tune Ca2+ signaling by facilitating crosstalk between Ca2+ channels at the cell surface with those on intracellular Ca2+ stores. Activation of α1-adrenergic receptors, expression of constitutively active Gαq (GαqQL), or PLCβ1b initiated cardiomyocyte hypertrophy and increased Homer 1c mRNA expression, by 1.6 ± 0.18-, 1.9 ± 0.17-, and 1.5 ± 0.07-fold, respectively (means ± SE, 6 independent experiments, P<0.05). Expression of Homer 1c induced an increase in cardiomyocyte area from 853 ± 27 to 1146 ± 31 µm² (P<0.05); furthermore, expression of dominant-negative Homer (Homer 1a) reversed the increase in cell size caused by α1-adrenergic agonist or PLCβ1b treatment (1503±48 to 996±28 and 1626±48 to 828±31 µm², respectively, P<0.05). Homer proteins were localized near the sarcolemma, associated with Shank3 and phospholipase Cβ1b. We conclude that Gq-mediated hypertrophy involves activation of PLCβ1b scaffolded onto a Shank3/Homer complex. Signaling downstream of Homer 1c is necessary and sufficient for Gq-initiated hypertrophy. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
38. Phospholipase Cβ1b associates with a Shank3 complex at the cardiac sarcolemma.
- Author
-
Grubb, David R., Iliades, Peter, Cooley, Nicola, Yen Lin Yu, Jieting Luo, Filtz, Theresa M., and Woodcock, Elizabeth A.
- Subjects
G proteins ,HEART cells ,HYPERTROPHY ,PROTEINS ,SARCOLEMMA ,SMALL interfering RNA - Abstract
Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell models. Our previous studies have shown that responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because only this PLC subtype localizes at the cardiac sarcolemma. In the current study, we investigated the proteins involved in targeting PLCβ1b to the sarcolemma in neonatal rat cardiomyocytes. PLCβ1b, but not PLCβ1a, coimmuno-precipitated with the high-MW scaffolding protein SH3 and ankyrin repeat protein 3 (Shank3), as well as the known Shank3-interacting protein-fodrin. The 32-aa splice-variant-specific C-terminal tail of PLCβ1b also associated with Shank3 and-fodrin, indicating that PLCβ1b binds via the C-terminal sequence. Shank3 colocalized with PLCβ1b at the sarcolemma, and both proteins were enriched in the light membrane fractions. Knockdown of Shank3 using siRNA reduced PLC activation and downstream hypertrophic responses, demonstrating the importance of sarcolemmal localization for PLC signaling. These data indicate that PLCβ1b associates with a Shank3 complex at the cardiac sarcolemma via its splice-variant-specific C-terminal tail. Sarcolemmmal localization is central to PLC activation and subsequent downstream signaling following Gq-coupled receptor activation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
39. Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase Cβ1b.
- Author
-
Filtz, Theresa M., Grubb, David R., McLeod-Dryden, Tiffany J., Jieting Luo, and Woodcock, Elizabeth A.
- Subjects
HYPERTROPHY ,HEART cells ,G proteins ,PHOSPHOLIPASE C ,INOSITOL ,DIGLYCERIDES ,PEPTIDES ,SARCOLEMMA - Abstract
Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell culture models. Hypertrophic responses induced by pressure or volume overload are exacerbated by increased Gq activity and ameliorated by Gq inhibition. Gq activates phospholipase Cβ (PLCβ) subtypes, resulting in generation of the intracellular messengers inositol(1,4,5)tris-phosphate [Ins(1,4,5)P
3 ] and sn-l,2-diacylglycerol (DAG), which regulate intracellular Ca2+ and conventional protein kinase C subtypes, respectively. Gq can also signal independently of PLCβ, and the involvement of either Ins(1,4,5)P3 or DAG in cardiomyocyte hypertrophy has not been unequivocally established. Overexpression of one splice variant of PLCβ1, specifically PLCβ1b, in neonatal rat cardiomyocytes causes increased cell size, elevated protein/ DNA ratio, and heightened expression of the hypertrophyrelated marker gene, atrial natriuretic peptide. The other splice variant, PLCβ1a, had no effect. Expression of a 32-aa C-terminal PLCβlb peptide, which competes with PLCβ1b for sarcolemmal association, prevented PLC activation and eliminated hypertrophic responses initiated by Gq or Gq-coupled α1 -adrenergic receptors In contrast, a PLCβ1a C-terminal peptide altered neither PLC activity nor cellular hypertrophy. We conclude that hypertrophic responses initiated by Gq are mediated specifically by PLCβ1b. Preventing PLCβ1b association with the sarcolemma may provide a useful therapeutic target to limit hypertrophy. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.