The goal of this program is to uncover the mechanism of the regulation of metal ion homeostasis, particularly magnesium homeostasis in vertebrates through the investigation of the structure and function of channel kinases. Channel kinases, also know as """"""""chanzymes"""""""" (channels plus enzymes) are recently discovered bifunctional molecules that consist of an ion channel fused to a protein kinase. Recent evidence suggests that channel kinases TRPM6 and TRPM7 play a key role in the regulation of metal ion homeostasis in vertebrates. Specifically, channel kinases have several major functions: 1) As magnesium channels they represent key regulators of magnesium homeostasis and may provide the major magnesium uptake mechanism in mammalian cells;2) As trace metal ion channels, channel kinases may provide a major ion channel mechanism for cellular entry of trace metal ions such as manganese and zinc. In Project 1 (Andrea Fleig, PI), we will perform biophysical, molecular, and functional analysis of the TRPM7 and TRPM6 ion channels. We will investigate molecular determinants of channel permeation that provide selectivity for divalent metal ions. In Project 2 (Alexey Ryazanov, 4PI), we will investigate the physiological function and mechanism of activation of TRPM7 and TRPM6 kinases. We will determine sequence motifs recognized by these kinases and identify their physiological substrates. In Project 3 (Andrew Scharenberg, PI) we will investigate the role of TRPM7 in the regulation of magnesium homeostasis. We will identify signaling pathways through which TRPM7 mediates magnesium-dependent regulation of cell and organism growth. In Project 4 (John Stokes, PI), we will analyze the role of TRPM6 and TRPM7 in the regulation of magnesium homeostasis using knockout mouse models. We will determine how magnesium balance affects kidney function in mice deficient in TRPM6 or TRPM7. We will also develop mice with conditional and organ-specific knockouts of TRPM6 and TRPM7. These projects will be supported by an Administrative Core (Core A), and an Animal and Analytical Core (Core B). This work has a high degree of medical relevance considering that channel kinases are likely to play a role in such conditions as ischemia and stroke, and since mutations in channel kinases are causing diseases associated with metal ion imbalance.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM078195-04
Application #
7843623
Study Section
Special Emphasis Panel (ZRG1-CB-K (40))
Program Officer
Anderson, Vernon
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$1,749,925
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Huang, Junhao; Furuya, Hideki; Faouzi, Malika et al. (2017) Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice. Cell Commun Signal 15:30
Antunes, Tayze T; Callera, Glaucia E; He, Ying et al. (2016) Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension. Hypertension 67:763-73
Turlova, Ekaterina; Bae, Christine Y J; Deurloo, Marielle et al. (2016) TRPM7 Regulates Axonal Outgrowth and Maturation of Primary Hippocampal Neurons. Mol Neurobiol 53:595-610
Zierler, Susanna; Sumoza-Toledo, Adriana; Suzuki, Sayuri et al. (2016) TRPM7 kinase activity regulates murine mast cell degranulation. J Physiol 594:2957-70
Jansen, Chad; Sahni, Jaya; Suzuki, Sayuri et al. (2016) The coiled-coil domain of zebrafish TRPM7 regulates Mg·nucleotide sensitivity. Sci Rep 6:33459
Ryazanova, Lillia V; Hu, Zhixian; Suzuki, Sayuri et al. (2014) Elucidating the role of the TRPM7 alpha-kinase: TRPM7 kinase inactivation leads to magnesium deprivation resistance phenotype in mice. Sci Rep 4:7599
Zhang, Zheng; Yu, Haijie; Huang, Junhao et al. (2014) The TRPM6 kinase domain determines the Mg·ATP sensitivity of TRPM7/M6 heteromeric ion channels. J Biol Chem 289:5217-27
Chu, Hsueh-Ping; Liao, Yi; Novak, James S et al. (2014) Germline quality control: eEF2K stands guard to eliminate defective oocytes. Dev Cell 28:561-572
Fleig, Andrea; Chubanov, Vladimir (2014) TRPM7. Handb Exp Pharmacol 222:521-46
Nikonorova, Inna A; Kornakov, Nikolay V; Dmitriev, Sergey E et al. (2014) Identification of a Mg2+-sensitive ORF in the 5'-leader of TRPM7 magnesium channel mRNA. Nucleic Acids Res 42:12779-88

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