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Thesis (Ph.D.). / Written for the Dept. of Neurology and Neurosurgery. Title from title page of PDF (viewed 2008/05/12). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [76]-87).

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 93-103).

Thesis (Ph. D.)--Cornell University, January, 2009. / Vita. Includes bibliographical references (leaves 126-137).

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [68]-80).

Morphological, electrophysiological and biochemical changes have been shown to occur in the retina, lateral geniculate nucleus, and visual cortex of light deprived animals. We attempted to determine whether the dark-rearing of rats from birth to 15, 30 and 60 days of age alters the ability of noradrenaline (NA) 30 μM, potassium chloride (KCI) 50 μM, adenosine 30 μM and combinations of NA and KCI with adenosine to stimulate the _in vitro formation of cyclic AMP (cAMP) in visual cortical slices and, as an internal control, in frontal cortical slices. At 15 and 30 days of age there was an 11% and 2170 reduction, respectively, compared to normally reared controls, in the stimulation of cAMP formation in a 5 minute incubation with NA in both frontal and visual cortical slices. After 60 days of dark-rearing, however, this was reversed in that the NA stimulation of cAMP formation was 23% and 357» higher than controls in frontal and visual cortical slices. In frontal cortical slices of rats dark-reared for 15 and 30 days there was a significant reduction in the stimulation of cAMP formation in a 20 minute incubation with NA. No differences were observed between 30 day old experimental and control animals in studies of the accumulation of cAMP in frontal and visual cortical slices incubated for various times with KCI. The stimulation of cAMP formation induced by KCI and adenosine in a 5 minute incubation was 5770 and 397o higher, respectively, in frontal cortical slices of 60 day old experimental animals than controls while the response in visual cortical slices was unaffected. The differences found between 60 day old experimental and control animals were abolished in both visual and frontal cortical slices when adenosine was used in combination with NA or KCI. Studies of the accumulation of cAMP in slices incubated for various times with NA revealed that the effect observed in the visual cortex after 30 days of light deprivation was due to a decrease in the maximum level of cAMP reached within a 20 minute incubation period, whereas in the frontal cortex the maximum level attained within a 20 minute incubation period was unaffected. These results are discussed in terms of our present knowledge concerning supersensitivity and plasticity in the central nervous system and the role of cAMP in nerve. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

In this thesis a detailed study of the kinetics of GnRH-stimulated LH release was made. GnRH stimulated LH release in a biphasic manner. During the first 3 minutes of stimulation, there was a transient spike phase of release followed by plateau phase of lower amplitude. Both phases of release are largely dependent on extracellular Ca²⁺. The spike phase of release is dependent on Ca²⁺ entry via a receptor-operated Ca²⁺ channel (ROCC) (about 90%) and on the mobilization of intracellular Ca²⁺ stores. The role of ROCC were examined by using ruthenium red which inhibits both ROCC and voltage-sensitive Ca²⁺ channels (VSCC). VSCC are not involved in the spike phase of GnRH-stimulated LH release since D600 and nifedipine, inhibitors of VSCC, have no effect on the spike phase. The plateau phase of release is dependent on Ca²⁺ entry via VSCC (about 50%) and ROCC (about 50%). Forskolin, an activator of adenylate cyclase, was used to investigate the role of cAMP in LH release. Forskolin stimulated an increase in both LH release and cellular cAMP levels. GnRH was also able to elevate the cellular CAMP concentration. GnRH interacted synergistically with forskolin to stimulate LH release. The synergism between GnRH and forskolin was not due to an interaction at (1) the GnRH receptor, (2) the level of intracellular Ca²⁺ mobilization, or (3) inositol phosphate metabolism. However, forskolin was able to synergistically interact with secretagogues that increase the cytosolic Ca²⁺ concentration and activators of protein kinase C. This suggested that forskolin was interacting with GnRH at a site distal to the activation of the Ca²⁺ second messenger system and protein kinase C. The data suggest that the initial response to GnRH is largely Ca²⁺-dependent and that other second messengers, if active, play a minor role. cAMP is thought to play a modulatory role and may be involved in the maintenance of secretion.

Yes / Caveolae are curved lipid raft regions rich in cholesterol and sphingolipids found abundantly in vascular endothelial cells, adipocytes, smooth muscle cells, and fibroblasts. They are multifunctional organelles with roles in clathrin-independent endocytosis, cholesterol transport, mechanosensing, and signal transduction. Caveolae provide an environment where multiple receptor signalling components are sequestered, clustered, and compartmentalised for efficient signal transduction. Many of these receptors, including cytokine signal transducer gp130, are mediators of chronic inflammation during atherogenesis. Subsequently, disruption of these organelles is associated with a broad-range of disease states including cardiovascular disease and cancer. Cavin-1 is an essential peripheral component of caveolae that stabilises caveolin-1, the main structural/integral membrane protein of caveolae. Caveolin-1 is an essential regulator of endothelial nitric oxide synthase (eNOS) and its disruption leads to endothelial dysfunction which initiates a range of cardiovascular and pulmonary disorders. While dysfunctional cytokine signalling is also a hallmark of cardiovascular disease, knowledge of caveolae-dependent cytokine signalling is lacking as is the role of cavin-1 independent of caveolae. This review will introduce caveolae, its structural components, the caveolins and cavins, their regulation by cAMP, and their potential role in cardiovascular disease.