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1. Bynagari, Yamini Saraswathy. Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets.
Degree: PhD, 2010, Temple University
Molecular and Cellular Physiology
Platelets are primary components of hemostasis. However, incongruous activation of platelets lead to thrombosis, which result in multiple cardio-vascular and cerebrovascular complications. Thus, platelet activation is tightly regulated. Molecular components that aid in activation of platelets have been extensively studied. However, molecular pathways that negatively regulate platelet activation and prevent accidental activation of platelets are poorly understood. In this study we investigated the molecular mechanisms that negatively regulate platelet activation. Protein Kinase C isforms (PKCs) are serine threonine kinases that regulate various platelet functional responses leading to hemostasis. Positive regulatory role of PKCs towards platelet aggregation and secretion has been extensively studied. However, we have recently demonstrated that PKCs negatively regulate ADP- induced thromboxane generation. The PKC isoforms and mechanism involved in this process have not been known. Thus, in this study we investigated the mechanism by which PKCs negatively regulate ADP-induced thromboxane generation and identified PKC isoforms that regulate thromboxane generation. Thromboxane generation in platelets is a multi-step process beginning with cPLA2 activation. cPLA2 activation is the rate limiting step in the process of thromboxane generation. Furthermore, cPLA2 activation is regulated by ERK and calcium in various cell systems including platelets. PKC inhibition potentiated both cPLA2 and ERK activation, suggesting that PKCs negatively regulate thromboxane generation by regulating ERK activation, which in turn regulates cPLA2 activation. Furthermore, we have also shown that PKCs negatively regulate ADP-induced calcium mobilization. ADP activates platelets via P2Y1 and P2Y12 receptors. P2Y12 receptor-mediated signaling is shown to positively regulate P2Y1-mediated calcium mobilization in platelets. Furthermore, PKCs are shown to negatively regulate P2Y12 receptor desensitization in platelets. Thus, we investigated if PKCs regulate calcium mobilization indirectly by regulating P2Y12 receptor function. However, PKCs regulate calcium mobilization independent of P2Y12 receptor signaling. In summary we have shown that PKC isoforms negatively regulate ADP-induced thromboxane generation by regulating calcium mobilization and ERK activation that in turn regulates cPLA2 activity. We further investigated the PKC isoforms involved in this process. Based on our results with Go-6976, a classical PKC inhibitor and GF109203X, a pan PKC inhibitor, we identified that that novel or atypical PKC isoforms are involved in negative regulation of ADP-induced thromboxane generation. Thus, we investigated the role of various novel class of PKC isoforms (nPKCs) in platelets. We first investigated the nPKCs activated by ADP. In aspirin-treated platelets, ADP failed to activate nPKC θ and δ non-stirring conditions. Thus, we conclude that these isoforms are not involved in negative regulation of thromboxane…Advisors/Committee Members: Kunapuli, Satya P., Driska, Steven Paul, Eguchi, Satoru, Daniel, James L., Bray, Paul F..
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APA (6th Edition):
Bynagari, Y. S. (2010). Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,103230
Chicago Manual of Style (16th Edition):
Bynagari, Yamini Saraswathy. “Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets.” 2010. Doctoral Dissertation, Temple University. Accessed October 22, 2020. http://digital.library.temple.edu/u?/p245801coll10,103230.
MLA Handbook (7th Edition):
Bynagari, Yamini Saraswathy. “Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets.” 2010. Web. 22 Oct 2020.
Bynagari YS. Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets. [Internet] [Doctoral dissertation]. Temple University; 2010. [cited 2020 Oct 22]. Available from: http://digital.library.temple.edu/u?/p245801coll10,103230.
Council of Science Editors:
Bynagari YS. Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets. [Doctoral Dissertation]. Temple University; 2010. Available from: http://digital.library.temple.edu/u?/p245801coll10,103230