Regulation of Calcium Entry in Cerebral Arteries

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9631416 Nelson Calcium ions within cells regulate muscle contraction, cell motility, cell proliferation and growth, and the secretion of hormones. The ("smooth") muscle cells that line the hollow organs of the body (e.g. blood vessels, airways, stomach, colon, bladder, uterus) contract when intracellular calcium raises, and relax when calcium falls. A decrease in the calcium within smooth muscle cells that comprise the wall of the arteries in the brain would lead to a dilation of the blood vessel, and increase in blood flow in the brain. The level of calcium in smooth muscle cells in arteries in the brain is regulated by the amount of calcium that enters these cells through specialized proteins in the cell membrane, called voltage-dependent calcium channels. Pharmacological agents such as the "calcium channel blockers" inhibit calcium entry through voltage-dependent calcium channels, and thus ultimately lead to vasodilation. One focus of Dr. Nelson's project is to understand how the cell's membrane potential (or "voltage") controls voltage-dependent calcium channels in smooth muscle cells from small brain arteries, under physiological conditions. The cell's membrane potential is key regulator of calcium entry, and thus exerts a profound control over blood vessel diameter. Dr. Nelson has recently discovered the calcium within these muscle cells is not uniform, and that rapid and high increases in intracellular calcium ("Calcium sparks") occur within about 1% of the cell's volume. These calcium sparks arise from the release of calcium through specialized proteins ("ryanodine-sensitive calcium release channel") in the membranes of compartments ("sarcoplasmic reticulum") within the cell. These calcium sparks appear to regulate indirectly calcium entry through alterations in the cell's membrane potential. Another goal of the project is to understand how voltage dependent calcium channels in the surface membrane regulate calcium sparks, and how calcium sparks in turn regulate calci um entry through voltage-dependent calcium channels. This work suggests a new paradigm for understanding the control of calcium entry in smooth muscle cells of arteries. Specifically, calcium entry through voltage-dependent calcium channels increases average calcium throughout a smooth muscle cell which leads to muscle contraction, and calcium entry also stimulates local increases in calcium ("calcium sparks"), which, through the membrane potential, acts as a negative feedback mechanism to decrease calcium entry. It would be the balance of these processes that would determine calcium entry, and ultimately blood vessel diameter. Dr. Nelson expects that these results would find parallels in other types of smooth muscle cells, in motile cells and in secretory cells, and should provide new insights in the control of cell function.