Regulated Secretion of BDNF

University Of Washington, Seattle WA

Investigators

Abstract

0078311 Bothwell It is currently believed that biologically active polypeptides, such as peptide hormones and growth factors, may be secreted by two alternative processes - an unregulatory secretory pathway and a regulated pathway, and it is thought that all polypeptides share the same regulated secretory mechanism. For cells that display regulated secretion of several different peptide hormones and growth factors, this model predicts that cells cannot regulate release of these polypeptides independently. Preliminary results indicate, however, that there must exist at least two distinct pathways for secretion of biologically active polypeptides, potentially allowing cells to independently control the release of hormones and growth factors that have different functions. The novel pathway is revealed by studies of the secretion of the neurotrophic factor, BDNF. Regulated secretion of BDNF by brain nerve cells is of profound importance, because BDNF participates as an important regulator of synaptic transmission in the context of memory and learning. The general goal of this proposal is to examine the mechanisms regulating secretion of BDNF in pituitary cells (which serve as a convenient model system for study of regulated secretion) and in nerve cells from the hippocampal and cortical regions of the brain. Secretion of BDNF will be compared to secretion of structurally related neurotrophic factors, NGF and NT-3. Also secretion of BDNF will be compared to secretion of neuropeptides, such as ACTH and NPY. Some experiments will directly monitor the release of these polypeptides, from cultured cells, using immunoassays. Other experiments will compare the distribution of these polypeptides in secretory vesicles within the cell, by immunohistochemical techniques. These studies may have broad importance for understanding hormone action in the endocrine system, and for understanding nerve cell communication in the brain. The orderly function of all tissues of the body is dependent on communication between cells. A major method of cell-cell communication involves secretion of specific polypeptides, which act as messenger molecules. The release of these polypeptides, which may be called peptide hormones, neuropeptides, or growth factors, must be carefully controlled. This project explores the possibility that cells can control release of these polypeptides much more cleverly than was realized previously. Thoroughly characterizing these controlled release mechanisms is essential for a basic understanding of biological processes ranging from hormone action to memory and learning.