Nerve cells use calcium ions to convert electrical signals into biochemical changes within the cell. Electrical activity increases intracellular calcium. Once inside the cell, calcium acts as a messenger carrying information to various parts of the cell interior where it acts to trigger processes ranging from gene expression to the release of neurotransmitters and hormones. Only during electrical stimulation, or during certain pathologies, is the calcium concentration in the cell elevated. Under normal conditions the intracellular calcium concentration is kept very low by a complex series of pathways which pump calcium out of the cell. The objective of this proposal is to study the modulation of three calcium regulatory processes. 1) Within the cell are specialized organelles that take up, store and release calcium. The signals that regulate the coupling of electrical activity at the cell surface to the release of calcium from these internal stores will be studied. 2) Another intracellular organelle that can take up calcium is the mitochondrion, the cell's powerhouse. Using recently developed methods to measure calcium within the mitochondrion, factors that influence mitochondrial calcium uptake will be determined. 3) Calcium loads are ultimately removed from the cell by pumps embedded in the cell-surface membrane. There are many genetic varieties of these pumps. It is not known how these variants differ functionally. The functional characteristics of individual pump variants, particularly their sensitivity to modulation, will be determined. To achieve these goals neurons will be grown in culture (in a dish), and studied individually with optical and electrophysiological instrumentation developed by the investigator. This work will increase our understanding of how neurons process information at the molecular and cellular level, and may reveal new targets for drugs.
