The role of caveolae in generating receptor-specific cyclic AMP signals in the adult cardiac myocyte

心脏泵血的能力是通过刺激心肌细胞膜上的受体来增强的，比如在运动过程中。这些作用被另一种受体，毒蕈碱受体所对抗。当这些受体受到刺激时，就会引发一系列事件，导致细胞膜上的电活动、钙在细胞周围的运动以及收缩元件之间的相互作用发生变化。所有这些过程结合在一起，对心脏细胞产生受体刺激的最终效果——心跳速率或力度的变化。有趣的是，尽管不同的受体对细胞有不同的作用，但它们通常共享一个共同的信号分子。和毒蕈碱受体都使用一种叫做环AMP （cAMP）的小分子。我们知道，对于每个受体来说，要通过cAMP实现其典型的反应，细胞内cAMP的变化必须在持续时间、大小和位置上具有受体特异性。我们认为，小泡是细胞膜上的小瓶状凹坑，在形成cAMP信号的特征中起着重要作用。小泡可以作为一个隔间，将产生或分解cAMP的蛋白质聚集在一起（并调节）。我们已经首次证明，当小泡从细胞膜上去除时，心脏细胞对β受体（β 2）和毒蕈碱受体（M2）亚型刺激的跳动反应受到影响。我们想了解小泡是如何对细胞中cAMP的控制施加影响的。我们的团队由英国和美国的研究人员组成，代表了独特的专业知识组合，这将使我们能够详细描述β 2和M2受体刺激产生的信号特征，以及这些信号如何转化为对细胞的功能影响。我们可以证明调节cAMP水平的蛋白质是否富集在膜的空洞部分。通过操纵小泡和使用药物来影响cAMP级联的不同部分，这项研究将使我们能够展示小泡如何塑造cAMP信号。因为小泡几乎存在于身体的所有细胞中，所以了解它们如何影响细胞信号传导是至关重要的。这项工作也对许多疾病（包括心脏病）具有深远的意义，这些疾病与小窝数量或功能的变化有关。

The ability of the heart to pump blood is increased by stimulation of beta receptors in the membrane of the heart muscle cell, for example, during exercise. These effects are opposed by another type of receptor, the muscarinic receptor. When these receptors are stimulated, a chain of events is initiated which leads to changes in electrical activity across the membrane, in the movement of calcium around the cell, and to interaction of contractile elements. All these processes combine to produce the ultimate effect of receptor stimulation on the heart cell - a change in the rate or force of beating. What is interesting is that although different receptors have different effects on the cell, they often share a common signaling molecule. Beta and muscarinic receptors both use a small molecule called cyclic AMP (cAMP). We know that for each receptor to achieve its typical response through cAMP, the changes in cAMP within the cell must be receptor-specific in terms of duration, size and location. We think that caveolae, which are small flask-like pits in the cell membrane, play an important role in shaping the characteristics of the cAMP signal. Caveolae can act as a compartment which brings together (and regulates) proteins which produce, or breakdown, cAMP. We have already shown for the first time that when caveolae are removed from the cell membrane, the beating response of the cardiac cell to stimulation of a subtype of beta receptor (beta2) and muscarinic receptor (M2) are affected. We want to understand how caveolae exert their influence on cAMP control in the cell. Our team, which consists of researchers in the UK and the USA, represents a unique combination of expertise which will allow us to describe in detail the characteristics of signals arising from beta2 and M2 receptor stimulation, and how these translate into functional effects on the cell. We can show whether proteins which regulate cAMP levels are enriched in the caveolar portion of the membrane. By manipulating caveolae and by using drugs to affect the different parts of the cAMP cascade, this study will allow us to show how caveolae shape cAMP signals. Because caveolae are found in almost all cells of the body, it is vital that we understand how they can affect cellular signaling. This work also has profound implications for many diseases (including heart diseases) which are associated with changes in the number or function of caveolae.