Different localizations may explain different physiological functions of the receptor

The heart has two different subtypes (beta 1 and beta 2) of beta adrenergic receptors that are activated by the stress hormones adrenaline and noradrenaline. Both of them cause the strongest stimulation of heart rate and pumping capacity that we know. The two subtypes are very biochemically similar, but differ significantly in terms of functional and therapeutic relevance.

Both receptor types can stimulate the heart in the short term, but long-term activation of the beta1 receptor has many effects not found in beta2. Beta1 can induce many persistent changes and has the ability to initiate cardiomyocyte growth (often harmful) by activating various genes.

Recent studies by researchers at the Universities of Wurzburg and Erlangen, the Maxdelbruck Molecular Medicine Center at the Helmholtz Association (MDC) in Berlin, and the ISAR Institute for Biological Sciences in Munich-Planek reveal the mechanisms behind these various effects. became.The research team published the results of their research in the latest issue of the journal Minutes of the National Academy of Sciences America’s.

Special ligands and new microscopy

“Using fluorescent ligands synthesized at the University of Arangen and new high-sensitivity microscopy, we were able to show for the first time where these receptors are located in cardiomyocytes,” said the Institute of Pharmacology and Toxicology. Professor Martin Rose explains. Julius-Maximilian University Würzburg (JMU). He is the co-lead author of this study, along with Dr. Paolo Annibale, who is responsible for the MDC’s Institute for Receptor Signal Transduction. “Intrinsic receptors are expressed at relatively low levels,” explains Annibale. “To detect those movements, we had to use a spectroscopic format based on the analysis of minute fluorescence fluctuations in the signal.”

This revealed that beta-1 receptors are found on the entire surface of cardiomyocytes, whereas beta2 receptors are found only in specific structures of these cells called T-tubules. These tubules create a pipe-like network through the interior of cardiomyocytes through invagination of the cell surface. “One of the focal points of our team’s research at MDC is the relationship between receptor function and intracellular localization,” adds Annibale. “Therefore, the biophysical environment of the transverse tubule with a curved membrane is of particular interest to us.”

Not all cardiomyocytes have beta1 receptors

“The specific intracellular location of the beta-2 receptor explains why it has a much narrower range of function than the beta1 receptor and why it is limited to direct and short-term stimulation of the heart,” Rose said. I will explain. Such stimuli are mediated by signals that are locally restricted to the cell membrane. In contrast, gene activation and cell proliferation stimulation occur via a broader range of signals that can only be triggered on the cell surface where only beta 1 receptors are present.

Another surprising finding in this study is that not all cardiomyocytes have these receptors. “Not all cells respond to adrenaline because cardiomyocytes have distinctly different types and states,” Rose said. Previously, all cardiomyocytes in large chambers were assumed to be the same.

New target for heart failure treatment

In chronic heart failure, it has long been known that adrenaline and noradrenaline circulate in the bloodstream and stimulate the heart to the extent that it causes changes in the heart and its cells. This initially compensates for heart failure, but in the long run overgrowth can damage the heart. Therefore, based in part on previous findings by the Würzburg team, blocking beta receptors has become an accepted treatment for chronic heart failure.

New discoveries show why beta1 receptors play a much greater role in producing these adverse effects than beta2 receptors. Beta1 receptors are localized across the cell surface and can have more diverse effects than beta2 receptors. New knowledge of the different localizations and distinct functional effects of beta1 and beta2 receptors in the heart may be used to develop better treatments for chronic heart failure. They selectively inhibit the harmful effects of beta receptors (such as cardiomyocyte growth) while activating beneficial effects (such as stimulating cardiac function).