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

点击翻译按钮获取中文摘要

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.