Project Summary

Gerald W. Zamponi, Ph.D. (Independent Investigator 2002) of University of Calgary, proposes to investigate in detail how dopamine receptors regulate N-type calcium channel activity, and thus communication in the central nervous system.  Calcium plays a number of highly important roles in human physiology.  In the brain, calcium entering into nerve cells controls nerve to nerve communication, but at the same time, too much calcium is toxic, and hence, the amount of calcium entering brain cells must be precisely controlled.  One key player in the regulation of calcium entry is a family of proteins termed “calcium channels”.  They are important pharmacological targets in a number of etiologies, and they have emerged as a factor in several hereditary disorders.  The N-type calcium channels are found in nerve endings where they are critical for the release of neurotransmitters.  Their activity, and consequently, the amount of neurotransmitter that is being released, is regulated by a number of neurotransmitter receptors, including dopamine receptors.  Abnormal dopamine receptor function has been implicated in several aspects of schizophrenia, and they are important targets in the treatment of this disorder.  His preliminary data indicates that different types of dopamine receptors mediate different effects on N-type calcium channels, with the D-2 dopamine receptor subtype inhibiting N-type channels effectively, whereas the D1 dopamine receptor does not.  Dr. Zamponi hypothesizes that D2 receptors and N-type calcium channels exist as preassembled protein complexes, and he plans to identify the underlying molecular determinants.  He plans to identify which parts of the D2 receptor are require for N-type calcium channel inhibition, exactly pinpoint the structures that are responsible for D2 receptor action, and determine whether a physical link between N-type calcium channels and D2 receptors occurs in living rat brain cells, using state of the art fluorescence imaging and microscopy techniques.  He believes his work will provide a number of novel insights into the action of dopamine receptors at the molecular level.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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