Cardiac Insufficiency: Mode of Operation of beta-receptors brought to light

Scientists at the Imperial College in London have, in cooperation with scientists from the University of Würzburg, succeeded in making characteristic alterations on pathological cardiac muscle cells visible in so far unequalled fidelity. Their images show that the normally deeply structured surface of the cardiac muscle flattens and, as a consequence, the processes within the cells change.

In a study published on February 26th in the renowned Science journal the researchers describe how they, as a first step, scanned the cardiac cells with a tiny pipette. From this emerges an image of the cell’s surface, depicting tiny nano-scaled details. Regularly arranged openings of pipe systems, so called transverse tubules, reaching far into the cell, are clearly visible. For quite a while has been known that at least two types of receptors for the stress hormone Adrenaline are existent on the surface of cardiac muscle cells. Both bring about a quicker and more robust heartbeat. But while one of them (beta-2) protects the heart, the other one (beta-1) appears to do damage to the organ. However, it has previously been unknown how these differences arise, for both receptor types have the same effect: they induce the production of cAMP in the cardiac muscle cells.

With their tiny pipettes the scientists have now succeeded in selectively stimulate the receptors on the surface as well as on the tubules directly. Thus they could examine how exactly the cAMP is generated subsequently. It became apparent that beta-2 receptors are located solely in tubules, whereas beta-1 receptors are distributed over the entire cell’s suface. Moreover, the scientists found that the tubules disappear progressively when a heart failure occurs and the beta-2 receptors get to the surface as a consequence. “in a pathological heart the beta-2 receptors generate adverse cAMP-signals spreading all over the cell instead of “good”, localized signals. In this case, they function exactly like beta-1 receptors”, explains Viacheslav Nikolaev, who developed the cAMP-sensor in Würzburg and afterwards conducted the experiments in London. “We know now, how beta receptors generate good and bad signals. Better beta-blocks or even entirely new medication is imaginable in order to treat cardiac failure.”

For their study, the scientists combined a highly sensitive scanning technique of the cell’s surface, that has been developed at the Imperial College be Julia Gorelik and Yuri Korchev, with a microscopical verification procedure for a central messenger substance within cardiac muscle cells, the so called cyclic AMP (cAMP). This procedure has been developed by the team around Martin Lohse at the Rudolf-Virchow-Center and the Pharmalogical Institute at Würzburg University – a fluorescent sensor in the cells shows the amount of the messenger substance cAMP.

Original Publication:
Redistribution of Beta-2 Adrenergic Receptors in Heart Failure Changes cAMP Compartmentation, Science, Friday 26 February 2010

Further Information Online:
http://www.pharmakologie.uni-wuerzburg.de/

Source: Rudolf-Virchow-Zentrum / DFG - Forschungszentrum für Experimentelle Biomedizin