Ion homeostasis and mechanisms of neurodegeneration.

Intracellular levels of essential ions such as calcium and transistion metals such as zinc are normally maintained at low levels because pronounced elevations in these ions has been shown to be neurotoxic. Calcium and zinc readily enter neurons via glutamate receptor and voltage gated Ca²⁺ channels. However, very little is understood about the role that plasma membrane transporters play in the overall cellular homeostasis of these two important ions.

A primary focus of the laboratory has been to identify the molecular mechanisms of plasma membrane transporters for zinc in cortical neurons, their role in zinc influx and efflux and the compartmentalization of zinc in neurons. Elevations of intracellular zinc may contribute to glutamate excitotoxicity and play a role in Alzheimer's pathology. We are using several different techniques to study zinc transport. These include direct measurement of the zinc transport function in plasma membrane vesicles purified from rat brain and in neurons in primary cell culture. We are also using imaging studies using fluorescent dyes to measure changes in intracellular zinc and pH. See our recent article characterizing zinc transport in cortical neurons (View PDF)

Another focus of the lab has been the plasma membrane sodium/calcium exchanger. The sodium/calcium exchanger is an important transport protein involved in cellular calcium homeostasis. The sodium/calcium exchanger is ubiquitously and highly expressed in rat brain (View PDF). Our laboratory was the first to report the possible correlation between Alzheimer's Disease pathogenesis and the sodium/calcium exchanger (Colvin, R.A., Bennett, J.W., Colvin, S.L., Allen, R.A., Martinez, J. and Miner, G.D. Na⁺/Ca²⁺ exchange activity is increased in Alzheimer's disease brain tissues. Brain Res. 543:139-147, 1991.). The sodium/calcium exchanger has been implicated in mechanisms of cell injury and death associated with glutamate toxicity. Glutamate excitotoxicity is thought to contribute to neuronal loss seen in cerebral ischemia and head trauma.

The laboratory has also investigated modulation of exchanger function in cell culture (e.g., effects of tyrosine kinase inhibition with genistein)(Wang, C., Davis, N., Colvin, R.A. Genistein inhibits Na⁺/Ca²⁺ exchange activity in primary rat cortical neuron cultures. Biochemical and Biophysical Research Communications 233:86-90, 1997). (View PDF).

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