Abstract

This project proposes to use genetic techniques to gain a better understanding of zinc metabolism in the mouse. A family of genes encoding transmembrane proteins that facilitate removal of zinc from the cytoplasm has been cloned. This family includes ZnT-1, which transports zinc out of the cell; ZnT-2, which facilitates accumulation of zinc in endosomal/lysosomal compartments, and ZnT-3, which was cloned by homology to ZnT-2 and is expressed in neuronal cells that sequester zinc in synaptic vesicles. These genes may play an essential role in protecting cells from excess zinc and/or facilitating the concentration of zinc in intracellular compartments where it may serve special functions. To test these hypotheses, the expression of these transporters will be analyzed, at both the tissue and cellular level, and that information will be used to help interpret the phenotypes of mice in which each of these genes is inactivated by homologous recombination. Mice lacking both zinc transporters and metallothioneins will also be generated to help define the role of these metal-binding proteins. The most exciting outcome of these experiments may be the demonstration that zinc has important neuromodulator functions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053013-02
Application #
2770652
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Haft, Carol Renfrew
Project Start
1997-09-29
Project End
2000-08-31
Budget Start
1998-09-23
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Gloyn, Anna L; Odili, Stella; Zelent, Dorothy et al. (2005) Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young. J Biol Chem 280:14105-13
Andrews, Glen K; Wang, Haibin; Dey, S K et al. (2004) Mouse zinc transporter 1 gene provides an essential function during early embryonic development. Genesis 40:74-81
Palmiter, Richard D (2004) Protection against zinc toxicity by metallothionein and zinc transporter 1. Proc Natl Acad Sci U S A 101:4918-23
Lopantsev, V; Wenzel, H J; Cole, T B et al. (2003) Lack of vesicular zinc in mossy fibers does not affect synaptic excitability of CA3 pyramidal cells in zinc transporter 3 knockout mice. Neuroscience 116:237-48
Lee, Joo-Yong; Cole, Toby B; Palmiter, Richard D et al. (2002) Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci U S A 99:7705-10
Cole, T B; Martyanova, A; Palmiter, R D (2001) Removing zinc from synaptic vesicles does not impair spatial learning, memory, or sensorimotor functions in the mouse. Brain Res 891:253-65
Cole, T B; Robbins, C A; Wenzel, H J et al. (2000) Seizures and neuronal damage in mice lacking vesicular zinc. Epilepsy Res 39:153-69
Cole, T B; Wenzel, H J; Kafer, K E et al. (1999) Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci U S A 96:1716-21