Robert A. Colvin, Ph.D.

     Intracellular levels of essential ions such as calcium and 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 plasma membrane Ca²⁺ and zinc transporters and their role in ion homeostasis.  One focus of the lab has been the 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 brains.  Our laboratory was the first to report the possible correlation between Alzheimer's Disease pathogenesis and the sodium/calcium exchanger (Colvin, R.A., et al., Brain Research 543:139-147, 1991).  We are currently defining the role of sodium/calcium exchange 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 is also investigating modulation of exchanger function in cell culture (e.g., effects of tyrosine kinase inhibition with genistein).

     Zinc is an essential trace element required as a co-factor for several metalloproteins (e.g., transcription factors, metalloenzymes).  Although intracellular zinc concentrations are normally maintained within a narrow range, very little is known about zinc transporters.  Elevations of intracellular zinc may contribute to glutamate excitotoxicity and play a role in Alzheimer's pathology.&nb sp; 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.

     Is there a genetic basis for the cognitive decline associated with aging? The genetic basis of behavior is an emerging field in neurobiology and our knowledge of the genetic basis of age related cognitive decline is very limited.  A separate project that we are involved in (in collaboration with the Edison Center at Ohio University) is trying to determine the genetic basis of the cognitive decline seen in aging rodents.  We will identify gene sequences differentially expressed in the brains of aging mice, create transgenic animals overexpressing these genes, and test their behavior as they age.  A second approach will use ovariectomized mice with or without estrogen replacement to identify gene sequences that are the basis for differences in cognitive ability.

Selected References:

• Colvin, R.A. Zinc inhibits Ca²⁺ transport by rat brain Na⁺/Ca²⁺ exchanger. Neuroreport 9:3091-3096 (1998).

• Colvin, R.A. Characterization of a plasma membrane zinc transporter in rat brain. Neuroscience Letters 247:147-150 (1998).

• Wu, A., Derrico, C.A., Hatem, L., Colvin, R.A. Alzheimer's amyloid-beta peptide inhibits sodium/calcium exchange measured in rat and human brain plasma membrane vesicles. Neuroscience 80:675-684 (1997).

• 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).

• Yu, L. and Colvin, R.A. Regional differences in expression of transcripts for Na⁺/Ca²⁺ exchanger isoforms in rat brain. Molecular Brain Research 50:285-292 (1997).