Alireza Poshtkohi;John Wade;Liam McDaid;Junxiu Liu;Mark L. Dallas;Angela Bithell
{"title":"小胶质细胞中 PI3K/Akt 通路的数学建模","authors":"Alireza Poshtkohi;John Wade;Liam McDaid;Junxiu Liu;Mark L. Dallas;Angela Bithell","doi":"10.1162/neco_a_01643","DOIUrl":null,"url":null,"abstract":"The motility of microglia involves intracellular signaling pathways that are predominantly controlled by changes in cytosolic Ca2+ and activation of PI3K/Akt (phosphoinositide-3-kinase/protein kinase B). In this letter, we develop a novel biophysical model for cytosolic Ca2+ activation of the PI3K/Akt pathway in microglia where Ca2+ influx is mediated by both P2Y purinergic receptors (P2YR) and P2X purinergic receptors (P2XR). The model parameters are estimated by employing optimization techniques to fit the model to phosphorylated Akt (pAkt) experimental modeling/in vitro data. The integrated model supports the hypothesis that Ca2+ influx via P2YR and P2XR can explain the experimentally reported biphasic transient responses in measuring pAkt levels. Our predictions reveal new quantitative insights into P2Rs on how they regulate Ca2+ and Akt in terms of physiological interactions and transient responses. It is shown that the upregulation of P2X receptors through a repetitive application of agonist results in a continual increase in the baseline [Ca2+], which causes the biphasic response to become a monophasic response which prolongs elevated levels of pAkt.","PeriodicalId":54731,"journal":{"name":"Neural Computation","volume":"36 4","pages":"645-676"},"PeriodicalIF":2.7000,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mathematical Modeling of PI3K/Akt Pathway in Microglia\",\"authors\":\"Alireza Poshtkohi;John Wade;Liam McDaid;Junxiu Liu;Mark L. Dallas;Angela Bithell\",\"doi\":\"10.1162/neco_a_01643\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The motility of microglia involves intracellular signaling pathways that are predominantly controlled by changes in cytosolic Ca2+ and activation of PI3K/Akt (phosphoinositide-3-kinase/protein kinase B). In this letter, we develop a novel biophysical model for cytosolic Ca2+ activation of the PI3K/Akt pathway in microglia where Ca2+ influx is mediated by both P2Y purinergic receptors (P2YR) and P2X purinergic receptors (P2XR). The model parameters are estimated by employing optimization techniques to fit the model to phosphorylated Akt (pAkt) experimental modeling/in vitro data. The integrated model supports the hypothesis that Ca2+ influx via P2YR and P2XR can explain the experimentally reported biphasic transient responses in measuring pAkt levels. Our predictions reveal new quantitative insights into P2Rs on how they regulate Ca2+ and Akt in terms of physiological interactions and transient responses. It is shown that the upregulation of P2X receptors through a repetitive application of agonist results in a continual increase in the baseline [Ca2+], which causes the biphasic response to become a monophasic response which prolongs elevated levels of pAkt.\",\"PeriodicalId\":54731,\"journal\":{\"name\":\"Neural Computation\",\"volume\":\"36 4\",\"pages\":\"645-676\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-03-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neural Computation\",\"FirstCategoryId\":\"94\",\"ListUrlMain\":\"https://ieeexplore.ieee.org/document/10535095/\",\"RegionNum\":4,\"RegionCategory\":\"计算机科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"COMPUTER SCIENCE, ARTIFICIAL INTELLIGENCE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neural Computation","FirstCategoryId":"94","ListUrlMain":"https://ieeexplore.ieee.org/document/10535095/","RegionNum":4,"RegionCategory":"计算机科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"COMPUTER SCIENCE, ARTIFICIAL INTELLIGENCE","Score":null,"Total":0}
Mathematical Modeling of PI3K/Akt Pathway in Microglia
The motility of microglia involves intracellular signaling pathways that are predominantly controlled by changes in cytosolic Ca2+ and activation of PI3K/Akt (phosphoinositide-3-kinase/protein kinase B). In this letter, we develop a novel biophysical model for cytosolic Ca2+ activation of the PI3K/Akt pathway in microglia where Ca2+ influx is mediated by both P2Y purinergic receptors (P2YR) and P2X purinergic receptors (P2XR). The model parameters are estimated by employing optimization techniques to fit the model to phosphorylated Akt (pAkt) experimental modeling/in vitro data. The integrated model supports the hypothesis that Ca2+ influx via P2YR and P2XR can explain the experimentally reported biphasic transient responses in measuring pAkt levels. Our predictions reveal new quantitative insights into P2Rs on how they regulate Ca2+ and Akt in terms of physiological interactions and transient responses. It is shown that the upregulation of P2X receptors through a repetitive application of agonist results in a continual increase in the baseline [Ca2+], which causes the biphasic response to become a monophasic response which prolongs elevated levels of pAkt.
期刊介绍:
Neural Computation is uniquely positioned at the crossroads between neuroscience and TMCS and welcomes the submission of original papers from all areas of TMCS, including: Advanced experimental design; Analysis of chemical sensor data; Connectomic reconstructions; Analysis of multielectrode and optical recordings; Genetic data for cell identity; Analysis of behavioral data; Multiscale models; Analysis of molecular mechanisms; Neuroinformatics; Analysis of brain imaging data; Neuromorphic engineering; Principles of neural coding, computation, circuit dynamics, and plasticity; Theories of brain function.