The regulation of a variety of biological processes ranging from muscle contraction to neuronal communication rely on virtually the same intracellular messengers. Nature has repeatedly used lipids, calcium, and cyclic nucleotides as modulators of cellular function. Bombarded with a multitude of extracellular signals, and having only a finite repertoire of messenger molecules, the cell needs to sort, integrate, and consolidate this information into a singular, coherent response. Alterations in this signal processing may be partially responsible for memory loss often observed in neurodegenerative disorders. The central nervous system is a prime example of the need for multiple signal processing. Conditional activation, the ability of one pathway to modulate another only when that other pathway is concurrently activate, may be an important regulatory mechanism for neurons to integrate temporal signals. Given the billions of neurons in the brain, however, a single scheme for regulating neurotransmission is insufficient to explain the multiplicities of tasks the brain carries out. Cell lines from the central nervous system, as opposed to brain slices or even primary cultures of neurons, do provide an experimental preparation amenable to biochemical manipulation. Studies of the regulation of second messenger production can be performed in these cells which represent single neural elements. Two such cell lines will he the focus of studies into the mechanism for the conditional regulation of cAMP production by protein kinase C. The goal of this project is to elucidate the biochemical mechanisms which underlie the storage and processing of information at the cellular level. A series of experiments, aimed at understanding the precise interactions between protein kinase C and cAMP signal transduction, will focus on neural cell lines with a defined composition of signal transduction components. The regulatory interactions observed in the intact cell will be confirmed by reconstitution in vitro with recombinant protein components. Differences in the regulation of second messenger production may be related to the isozyme composition of the signal transduction components or the organization of those components. These differences may allow particular cells to integrate a variety of cellular stimuli, thus providing the diversity of regulatory mechanisms necessary for the brain to perform complex tasks. Although the complexity of cognitive memory can not be solved solely by studies of neural cell lines, a biochemical description of the regulation of neural signal transduction will illuminate potential mechanisms for synaptic plasticity that would be inherently difficult to study in other experimental preparations. Once the mechanisms for information storage and processing are understood in cell culture models, subsequent tests in experimental preparations more amenable to classical behavioral studies should shed more insight into the generalities of memory biochemistry, and eventually lead to a fundamental understanding of neural plasticity.
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| Hurst, W J; Moroz, L L; Gillette, M U et al. (1999) Nitric oxide synthase imunolabeling in the molluscan CNS and peripheral tissues. Biochem Biophys Res Commun 262:545-8 |
| Nichols, M R; Morimoto, B H (1999) Tyrosine kinase-independent inhibition of cyclic-AMP phosphodiesterase by genistein and tyrphostin 51. Arch Biochem Biophys 366:224-30 |
| Stringfield, T M; Morimoto, B H (1997) Modulation of cyclic AMP levels in a clonal neural cell line by inhibitors of tyrosine phosphorylation. Biochem Pharmacol 53:1271-8 |
