Metabolic memory: the CaMKII role in the LTP generation in pancreatic islet

• Grant number: 12/13434-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: March 10, 2013
• End date: October 09, 2013
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Antonio Carlos Boschiero
• Grantee: Gustavo Jorge dos Santos
• Supervisor: Klaus H. Kaestner
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Pennsylvania, United States

Abstract

The calcium ion (Ca2 +) acts as a mediator of cell signaling in all eukaryotic cells, regulating various functions such as proliferation, gene expression, and exocytosis. This signal must be in perfect condition and is mainly regulated by Ca2+ Binding Proteins (Ca2+BP). The main representative of these proteins is the Calmodulin, that's responsible to turn enables/disables protein kinase as the Ca2+/Calmodulin Kinase II (CaMKII). The CaMKII is a holoenzyme comprised of approximately 10 subunits and there are four different isoforms (±, ², ³, ´) for this enzyme. The ± and ² subunit are expressed mainly in the CNS and in pancreatic ² cells, both the subunit ² as ´ are present. The enzyme is formed by the catalytic, regulatory, regulatory and an association domain. At baseline, CaMKII is self-inhibited, when Ca2+ intracellular concentrations rise occurs a connection between CaMKII and the Ca2+/Calmodulin complex, leading a conformational change in CaMKII's structure, promoting an auto-phosphorylation of the enzyme. By presenting these properties (auto-inhibition and auto-phosphorylation) CaMKII is considered to be the protein responsible for formation of LTP (Long-Term potentiation), the main engine pointed in memory formation. Moreover, CaMKII is known to be the key to a proper insulin secretion, because this enzyme is part of the processes that culminate in the extrusion of insulin granules, regulating SNARES activity. It is also known that CaMKII activity is directly related to increased in glucose-stimulated insulin secretion. Although clearing the hypothesis that pancreatic ² cells and neurons have the same embryonic origin, one cannot deny that there are many features in common between these two cell types. The insulin-producing cells express several proteins with secretory function present in neurons that are modulated by CaMKII. Moreover, ² cells express receptors for several growth factors nervous. Given that, we believe that CaMKII may perform, in pancreatic ² cells, similar functions performed in LTP formation observed in neurons. In other words, we will investigate if there are in pancreatic ² cells molecular mechanisms similar of LTP, resulted of high glucose exposure, similar that is observed in memory formation, and moreover, if these potential mechanisms are related to metabolic disorders like obesity. (AU)