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Coupling of calcium (Ca²⁺) release by ryanodine receptor (RyR) 3 to its extrusion by sodium/calcium exchanger (NCX) mediates endoplasmic reticulum (ER) Ca²⁺ discharge from vascular endothelial cells

University of British Columbia

The endoplasmic reticulum (ER) is an organelle with multiple functions serving to maintain cellular health, the most important of which include its role as the cell’s largest store of the signaling ion calcium (Ca²⁺). The regulation of this ion’s movement into and out of the ER, as well as the cell itself, is therefore of the utmost importance when considering the overarching goal of each cellular body to remain functional. The study outlined in the current thesis discusses hypotheses for the manner in which Ca²⁺’ is released in a dramatic dysregulation event during ER stress, a cellular condition that often results in cell death and which has been implicated in multiple severe health conditions. This pathway was chosen to be studied in endothelial cells (ECs), those comprising the intimal (inner-most) layer of blood vessels. These cells are in direct contact with blood flowing through these tributaries of the vasculature, and their vast array of products controls constriction and many other properties of the blood vessel itself. Dysfunction of these cells results in the loss of their ability to exert protective effects on the affected blood vessel. Importantly, this type of damage to ECs can occur as a result of Ca²⁺ dysregulation at the level of the ER, such as the dramatic ER Ca²⁺ drop being studied here. It is therefore the aim of the current thesis to present evidence for the mechanism whereby dramatic changes in Ca²⁺ levels within the ER lead to problems cellular function, with the ultimate goal of therapy development to prevent affected cells from becoming dysfunctional as a result of such ion dysregulation. Investigation into the way that cytoplasmic and luminal ER Ca²⁺ levels are affected by a range of agonists as well as relevant channel and pump blockers has culminated in a clearer understanding of the likely pathway for this Ca²⁺ movement early in the ER stress response, which may in future be manipulated at the point of ER stress induction to potentially deter subsequent cell failure, and ultimately, vascular disease.

Text

2018-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/64339

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/