Differential regulation of adenylyl cyclase by Ca2+ entry and Ca2+ release in arterial smooth muscle.

动脉平滑肌中 Ca2+ 进入和 Ca2+ 释放对腺苷酸环化酶的差异调节。

• 批准号: G0700843/1
• 负责人: Colin Taylor
• 金额: $ 47.27万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700843%2F1
• 关键词: Differential; regulation; adenylyl; cyclase; Ca2+

Cells are bombarded by signals continuously telling them about the outside world. Rarely do these signals penetrate the barrier (the plasma membrane) that surrounds each cell, rather they bind to proteins within plasma membrane to cause changes in the concentration of intracellular messengers. Hundreds of stimuli succeed in precisely regulating cellular activities using just a handful of intracellular messengers. How do so few intracellular messengers suffice to mediate specific responses to so many signals? The answer is, at least partly, due to the spatial and temporal organization of the intracellular signals. The temporal pattern of the messenger affects the response, and a signal evoked in one part of the cell may trigger different responses to that evoked elsewhere. This proposal is concerned with interactions between two ubiquitous intracellular messengers, Ca and cAMP, and the mechanisms that allow Ca passing through different Ca channels to exert very different effects on the enzyme (AC) responsible for cAMP formation. The work focuses on vascular smooth muscle, where Ca and cAMP together regulate both contraction (and so blood pressure) and proliferation. We have shown that Ca released via channels within intracellular Ca stores evokes a short-lasting Ca signal that triggers a long-lasting inhibition of cAMP formation. By contrast, Ca entering cells across the surrounding membrane causes acute inhibition of cAMP formation that reverses as soon as the Ca signal terminates. We suggest that the two Ca channels direct Ca to different forms of AC in different parts of the cell to produce acute or long-lasting inhibition of AC activity. Our aim is to establish the determinants of this behaviour, which highlights the spatial and temporal organisation of two of the most important signalling pathways and the interactions between them.

细胞不断地被告知外界世界的信号轰炸。这些信号很少穿透每个细胞周围的屏障(质膜)，而是与质膜内的蛋白质结合，导致细胞内信使浓度的变化。成百上千的刺激物仅使用几个细胞内信使就能成功地精确调节细胞活动。为什么这么少的细胞内信使足以调节对这么多信号的特定反应？答案是，至少部分是由于细胞内信号的空间和时间组织。信使的时间模式影响反应，在细胞的一个部分引起的信号可能会触发对其他地方引起的不同反应。这一建议涉及两个普遍存在的细胞内信使--钙和cAMP之间的相互作用，以及允许钙通过不同的钙通道对负责cAMP形成的酶(AC)产生截然不同的影响的机制。这项研究的重点是血管平滑肌，在那里，钙和cAMP共同调节收缩(以及血压)和增殖。我们已经证明，通过细胞内钙库内的通道释放的钙能激发一种短暂的钙信号，从而触发对cAMP形成的长期抑制。相反，钙跨过周围细胞膜进入细胞会引起cAMP形成的急剧抑制，一旦钙信号终止，cAMP的形成就会逆转。我们认为，这两种钙通道将钙引导到细胞不同部位的不同形式的AC中，从而对AC活性产生急性或持久的抑制。我们的目标是确定这种行为的决定因素，突出两条最重要的信号通路的空间和时间组织以及它们之间的相互作用。