Cellular and Molecular Mechanisms of Transient Receptor Potential Melastatin 7 (TRPM7) Channel in Neuronal Development and Injury
Year: 2018
Type: dissertation
Abstract: Transient Receptor Potential Melastatin 7 (TRPM7) is a ubiquitously expressed, calcium-permeable ion channel that regulates intracellular levels of divalent cations, cytoskeletal dynamics, cell adhesion and other processes. As these processes are critical for neurite elongation during development, this thesis investigated the role of TRPM7 in neurite outgrowth and development using a pharmacological approach. It was found that blocking TRPM7 activity preferentially enhanced axonal outgrowth of cultured hippocampal neurons at least in part through TRPM7 interaction with cytoskeletal proteins, actin and α-actinin. TRPM7 activity is potentiated under the conditions of stress that commonly occur in injury or disease, such as increased extracellular acidity and production of reactive oxygen species. Therefore, the effect of hypoxia, a common cause of damage to the developing brain, on TRPM7 activity and TRPM7-mediated neurite outgrowth was investigated next. It was found that prolonged hypoxia caused axonal retraction, while blocking TRPM7 activity attenuated this effect. Finally, the therapeutic potential of TRPM7 blocker has been evaluated in a mouse model of neonatal hypoxic-ischemic brain injury, and blocking TRPM7 pharmacologically had neuroprotective and therapeutic effects (up to 1 hour after injury). Further short and long-term evaluation demonstrated preservation of brain morphology and functional motor and memory outcomes. Proteomic analysis revealed that TRPM7 may mediate neuronal injury at least in part through calcium-dependent cytoskeletal regulation by calcium/calmodulin-dependent kinase and phosphatase. Overall, this thesis establishes the role of TRPM7 in neuronal outgrowth and development under normal and stress conditions. Moreover, it evaluates a specific pharmacological inhibitor of TRPM7 as a candidate for further drug development for hypoxic-ischemic injury to the developing brain.
Source: TSpace (University of Toronto)
Author: Ekaterina Turlova
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3161859109