Regulation of Calcium Entry in Cerebral Arteries

脑动脉钙进入的调节

• 批准号: 9631416
• 负责人: Mark Nelson
• 金额: $ 19.97万
• 依托单位: University of Vermont & State Agricultural College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9631416&HistoricalAwards=false
• 关键词: Regulation; Calcium; Entry; Cerebral; Arteries

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.

小行星9631416纳尔逊 细胞内的钙离子调节肌肉收缩、细胞运动、细胞增殖和生长以及激素的分泌。 排列在身体中空器官（例如血管、气道、胃、结肠、膀胱、子宫）上的（“平滑肌”）细胞在细胞内钙升高时收缩，并且在钙福尔斯降低时松弛。 构成大脑动脉壁的平滑肌细胞内的钙减少会导致血管扩张，并增加大脑中的血流量。 大脑动脉中平滑肌细胞中的钙水平由通过细胞膜中的专门蛋白质（称为电压依赖性钙通道）进入这些细胞的钙量调节。 药理学试剂如“钙通道阻断剂”抑制钙通过电压依赖性钙通道进入，并因此最终导致血管舒张。 纳尔逊博士项目的一个重点是了解细胞的膜电位（或“电压”）如何在生理条件下控制来自小脑动脉的平滑肌细胞中的电压依赖性钙通道。 细胞的膜电位是钙进入的关键调节器，因此对血管直径有着深远的控制。 纳尔逊博士最近发现，这些肌肉细胞内的钙是不均匀的，并且细胞内钙的快速和高增加（“钙火花”）发生在细胞体积的约1%内。 这些钙火花来自于通过细胞内隔室（“肌浆网”）膜中的专门蛋白质（“鱼尼汀敏感性钙释放通道”）释放钙。 这些钙火花似乎通过改变细胞膜电位间接调节钙的进入。 该项目的另一个目标是了解表面膜中的电压依赖性钙通道如何调节钙火花，以及钙火花如何反过来调节卡尔奇通过电压依赖性钙通道的进入。这项工作为理解动脉平滑肌细胞中钙离子进入的控制提供了一个新的范例。 具体地，通过电压依赖性钙通道的钙进入增加整个平滑肌细胞的平均钙，这导致肌肉收缩，并且钙进入还刺激钙的局部增加（“钙火花”），其通过膜电位充当负反馈机制以减少钙进入。 正是这些过程的平衡决定了钙的进入，并最终决定了血管直径。 纳尔逊博士预计，这些结果将在其他类型的平滑肌细胞，运动细胞和分泌细胞中找到相似之处，并应提供控制细胞功能的新见解。