Juliusz Ashot Kozak, Ph.D. (Advisor); Christopher N. Wyatt, Ph.D. (Committee Member); David R. Ladle, Ph.D. (Committee Member)
Master of Science (MS)
Humans are exposed daily to a variety of metals that can be harmful to our immune system. Although certain divalent metal cations are essential for numerous cellular functions and are critical trace elements in humans, the uptake mechanisms of these ions remain mostly unknown. Transient receptor potential melastatin 7 (TRPM7), which is expressed in a variety of human cell types, including lymphocytes and macrophages, conducts many divalent metal cations. TRPM7 channels are largely inactive under normal physiological conditions due to cytoplasmic magnesium acting as a channel inhibitor. Magnesium is a cofactor for many biochemical reactions. Low serum levels of magnesium, hypomagnesemia, can occur from increased magnesium loss from renal or gastrointestinal systems, redistribution of magnesium across the cell membranes, and decreased magnesium intake. Magnesium depletion allows both physiological and non-physiological divalent metal cations to enter through TRPM7, which is highly expressed in T-lymphocytes. Alterations to TRPM7 channel activity by channel blockers were found to affect the cell viability sequence. Through the use of Jurkat, a leukemic T-lymphocyte cell line which expresses high levels of TRPM7, HAP1 cells, and a TRPM7 kinase-dead mouse model, the entry of both physiological and non-physiological cations can be quantitated by measuring cell toxicity. A cell toxicity/viability assessment in Jurkat T-lymphocytes provided the sequence of Cd2+ > Zn2+ > Co2+ > Ni2+ > Mn2+ >> Sr2+ ≈ Ba2+ ≈ Ca2+ ≈ Mg2. Homeostatic mechanisms alter the effects of divalent metal cation entry and viability of T-lymphocytes, suggesting that TRPM7 in part contributes to metal ion entry.
Department or Program
Department of Neuroscience, Cell Biology, and Physiology
Year Degree Awarded
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