Previous investigations have demonstrated that besides the intestine at least 20 tissues including brain all have receptors for 1,25dihydroxyvitamin D3 (1,25(OH)2D3) and/or a vitamin D induced calcium binding protein (CaBP), thus suggesting a wider role for vitamin D in calcium metabolism than mere intestinal calcium absorption. The object of this proposal is to obtain a better understanding of the role of the calcium homeostat steroid hormone, 1,25(OH)2D3 in specific brain function and in the control of epileptogenic activity. Specifically we will study the effect of alterations in the vitamin D endocrine system on seizure activity and threshold. Brain regions functionally activated by 1,25(OH)2D3 administration will be analyzed by (14C) 2-deoxyglucose (2DG). In a related study we will examine how 1,25(OH)2D3 administration might alter the spread of epileptiform activity as determined by 2DG autoradiography. The effect of 1,25(OH)2D3 on activities of monamine oxidase and choline acetylase in specific brain nuclei will be determined. In an effort to determine the functional significance of the vitamine D dependent calcium binding protein (CaBP) in brain, the ability of CaBP to stimulate synaptic vesicle neurotransmitter release and protein phosphorylation will be examined. The interaction of CaBP with cellular and particulate constituents of various brain regions will be investigated and the brain proteins bound to CaBP and those bound to calmodulin will be compared using an SDS gel overlay technique. Finally, previous studies concerning alterations in brain CaBP with kindling induced seizures will be extended. We will determine molecular mechanisms involved in an alteration in CaBP and whether other proteins or gene products are affected by kindling induced seizures in specific brain regions. It is likely that important advances to the understanding of epilepsy can be made by examining molecular level changes and that molecular genetics will play an increasingly important role in the elucidation of the mechanism of control of the epileptic state.
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