Project 4: Mechanisms of Mg2+ Homeostatis: Mouse Models

镁对每个哺乳动物细胞都至关重要。它是蛋白质的重要辅助因子

Magnesium is of critical importance to every mammalian cell. It is an important cofactor for protein synthesis, nucleic acid synthesis and stability, energy utilization, and membrane excitability. Despite its biological importance, relatively little is known about how Mg homeostasis is regulated. In the past few years investigators have uncovered three genes that, when mutated, form the genetic basis for familial disorders leading to hypomagnesemia. One of those genes, TRPM6, was uncovered by work done at the University of Iowa and published simultaneous with, and independent of, a group from Marburg, Germany. Loss of this gene product leads to the syndrome of hypomagnesemia with secondary hypocalcemia. This TRPM6 gene product appears to form a Mg channel when it interacts with at least one other protein, TRPM7. The major locations where TRPM6 is expressed, the colon and renal distal convoluted tubule, support the notion that these proteins play a major role in absorption and excretion of Mg. As a Project 4 in a Program to elucidate the role of TRPM6 and TRPM7 in Mg homeostasis, we hypothesize that these two proteins interact to enhance Mg absorption by intestine and renal distal convoluted tubule cells. We also hypothesize that the alpha kinase domains of both proteins serve a critical role in regulating Mg transport in absorptive cells. We also propose that Mg deficiency and the alpha kinase domains play important roles in regulating cell functions not directly related to channel transport function. The proposed studies will initiate a detailed assessment of how these gene products function in mouse models with a disrupted TRPM6 and TRPM7 genes. The proposed experiments will test specific hypotheses related to how this gene functions in Mg depletion, how its dysfunction and hypomagnesemia in general produce hypokalemia, and how the TRPM6 gene product influences development of the mouse. The specific aims are: 1) Determine how Mg balance affects the segmental nephron function in normal mice and mice with disrupted TRPM6 and TRPM7 genes; 2) Develop mouse models with a conditionally inactivated TRPM6 and TRPM7 genes.