Abstract

Glial cells display propagated waves of cytoplasmic calcium (Ca2+) mobilization that spread outward from an initiating cell to involve hundreds to thousands of surrounding cells. This intercellular communication system is thought to initiate and coordinate Ca2+ dependent processes associated with vascular control, gut motility, uterine contraction, and synaptic plasticity. Not surprisingly, aberrant Ca signaling is thought to play a featured role in the pathophysiologies associated with dysfunction of these processes. This suggests that elucidation of the mechanism of Ca2+ waves will lead to rational therapeutic modalities for a variety of clinically significant entities.

Early studies revealed that Ca2+ waves in glia require the expression and function of the gap junction protein connexin43 (Cx43), the function of phospholipase C (PEC) and the mobilization of Ca2+ from inositol-1,4,5-trisphosphate (IP3) dependent stores. This lead to the hypothesis that Ca waves are mediated by mobilization of IP3 in the stimulated cell that then diffuses to surrounding cells through gap junctions composed of Cx43 where it initiates Ca2+ mobilization from IP3 dependent stores. Subsequently, this hypothesis was confounded by the discovery that Ca2+waves are mediated by ATP diffusion in the extracellular space. This confusion arose because Cx43 channels are most studied in the gap junction configuration and no role could easily be ascribed to an intercellular channel in an extracellular paracrine signaling system. Cx43 channels also exist, however, in a hemichannel configuration that gates between the cytoplasm and the extracellular space.

The main discovery of this dissertation is that it is the hemichannel configuration that is required for Ca2+ waves. Specifically, Cx43 hemichannels mediate the release of ATP into the extracellular space to initiate and sustain glial Ca2+ waves. Further, it is demonstrated that diacylglycerol mobilization is associated with hemichannel activation 9-f- indicating a new role of PLC activity in Ca2+ wave propagation. Finally, modulation of this ATP release pathway by several agents, including those with clinical significance, is 9-4- demonstrated to be directly correlated with modulation of Ca wave propagation suggesting that modulation of ATP release represents a viable target for rational therapeutic treatment of disorders that arise from aberrant Ca2+ signaling.

LLU Discipline

Physiology

Department

Physiology

School

Graduate School

First Advisor

J. Mailen Kootsey

Second Advisor

Andrew Charles

Third Advisor

John Buchhlolz

Fourth Advisor

George Maeda

Fifth Advisor

William J. Pearce

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2002

Date (Title Page)

3-2002

Language

English

Library of Congress/MESH Subject Headings

Astrocytes -- physiology; Calcium Channels -- metabolism; Calcium Signaling.

Type

Dissertation

Page Count

x; 145

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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