Mechanisms of Calcium Wave Initiation and Propagation in Astrocytes

<p>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.</p> <p>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.</p> <p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Physiology

Year

2002

Author dc:creator

• Stout, Charles Emmet

Contributors dc:contributor

• J. Mailen Kootsey
• Andrew Charles
• John Buchhlolz
• George Maeda
• William J. Pearce

• Cellular and Molecular Physiology
• Astrocytes -- physiology; Calcium Channels -- metabolism; Calcium Signaling.

Statement dc: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.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/925

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1899