The location of the receiver plays a key role in their function

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PICTURE: Beta1 and beta2-adrenergic receptors in heart muscle cells: In the left cell, beta1 receptors are labeled – they are found both on the cell surface (yellow) and in the T tubules … see After

Credit: Marc Bathe-Peters & Horst-Holger Boltz

In the heart, there are two different subtypes of beta-adrenergic receptors – beta1 and beta2 – which are activated by the stress hormones epinephrine and norepinephrine. They both trigger the strongest stimulation in heart rate and pumping capacity that we know of. The two subtypes are very similar biochemically, but differ considerably in terms of functional and therapeutic relevance.

Both types of receptors can stimulate the heart in the short term, but when the beta1 receptor is activated over an extended period of time, it has a range of effects that are not seen with beta2. Beta1 can cause a number of persistent changes and is endowed with the ability to initiate – often detrimental – the growth of heart muscle cells by turning on various genes.

Recent studies by researchers at the universities of Würzburg and Erlangen, the Max Delbrück Center for Molecular Medicine at the Helmholtz Association (MDC) in Berlin and the ISAR Bioscience Institute in Munich-Planegg have now shed light on the mechanisms at the origin of these different effects. The research teams have published the results of their work in the current issue of the journal Proceedings of the National Academy of Sciences the United States.

Special ligands and new methods of microscopy

“Using a fluorescent ligand synthesized at the University of Erlangen and new highly sensitive microscopy methods, we were able to show for the first time where these receptors are located on heart muscle cells,” explains the Professor Martin Lohse of the Institute of Pharmacology and Toxicology at the Julius Maximilians University in Würzburg (JMU). He is the co-lead author of the study with Dr. Paolo Annibale, who is acting head of the MDC receptor signaling laboratory. “Endogenous receptors are expressed at relatively low levels,” says Annibale. “To detect their movement, it was necessary to use a form of spectroscopy based on the analysis of minute fluorescence fluctuations of the signal.”

This revealed that beta1 receptors are found all over the surface of heart muscle cells, while beta2 receptors are found exclusively in specific structures of these cells called T tubules. Through invaginations of the cell surface, these tubules create a a pipe-like network that runs through the interior of the heart muscle cells. “One of the areas of research of our team at MDC is the relationship between receptor function and subcellular localization,” adds Annibale. “So the biophysical environment of T-tubules, which have curved membranes, is of particular interest to us.”

Not all heart muscle cells have beta1 receptors

“The specific cellular location of beta2 receptors explains why they have a much narrower range of functionality than beta1 receptors and why they are limited to direct, short-term stimulation of the heart,” explains Lohse. Such stimulation is mediated by signals which are locally limited to the cell membrane. In contrast, gene activation and stimulation of cell growth occur via more extensive signals that can only be triggered at the cell surface, where only beta1 receptors are located.

Another surprising finding from the study is that not all heart muscle cells have these receptors. “There are apparently different types or states of heart muscle cells, so not all cells respond to adrenaline,” Lohse said. Until now, it was assumed that the heart muscle cells in the large chambers were all the same.

New target for the treatment of heart failure

It has been known for many years that in chronic heart failure, too much adrenaline and norepinephrine circulate in the blood and stimulate the heart to such an extent that it causes changes in the heart and the growth of its cells. This initially compensates for heart failure, but in the long run, the excess growth damages the heart. Therefore, based in part on earlier findings by the Würzburg team, blocking beta receptors has become the accepted therapy for chronic heart failure.

The new findings now show why beta1 receptors play a much larger role in producing these unwanted effects than beta2 receptors. Beta1 receptors are located all over the cell surface, which allows them to have a more diverse impact than beta2 receptors. New knowledge about the differential localization and distinct functional effects of beta1 and beta2 receptors in the heart could potentially be exploited to develop better therapies for chronic heart failure. These would selectively inhibit the harmful effects of beta receptors (such as the growth of heart muscle cells), while activating the beneficial effects (such as stimulation of heart function).

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