The connexin43 nexus: Regulation of a junctional complex

Abstract

Gap junction channels have traditionally been thought to function solely as conduits for transport of ions and small molecules between adjacent cells. Therefore, much of the current work in the field focuses on properties of the channel itself or on factors that control expression levels of the channel proteins (connexins) or their mRNA. However, protein-protein interactions are increasingly appreciated as playing major roles in regulating functions of other proteins including other ion channels. Recent evidence indicating that some connexins interact with other proteins suggests a novel mechanism for connexin regulation. Such interactions are the focus of this thesis research.;Connexin43 (Cx43) is the major gap junction protein found in many cell types, including astrocytes. My work has examined the role of connexin binding partners in the chemical regulation of Cx43 in astrocytes. In the first two chapters I describe the effects of two distinct treatments, cytokine application and intracellular acidification on levels and localization of Cx43 as well as other junctional proteins in astrocytes. In the third chapter I describe work on determining the structure of the Cx43 and its interdomain protein-protein interactions and suggest a model for the chemical gating of gap junction channels formed from this important gap junction protein. The specific hypothesis of this thesis research is that protein-protein interactions play a key role in chemical regulation of junctional complexes and that Cx43-protein interactions may be involved in astrocytic responses to brain injury.