Teams of researchers in Erlangen, Würzburg, Munich and Berlin have determined the location of special receptors on cardiac muscle cells for the first time. Their findings open up new possibilities for treating chronic cardiac insufficiency.
There are two different subtypes of beta adrenergic receptors in the heart, beta1 and beta2, which are activated by the stress hormones adrenalin and noradrenalin. Both trigger the strongest stimulation of the strength and frequency of the heart rate that we know. Although both subtypes are very similar to each other in biochemical terms, they vary greatly in terms of their function and therapeutic effects. Although both receptor types can stimulate the heart in the short term, the beta1 receptor can trigger a series of long-term changes if activated over a longer period of time, which can often cause harmful growth of cardiac muscle cells due to the activation of various genes. This does not apply to the beta2 receptor.
The latest investigations by a research team from the universities of Erlangen and Würzburg, the Max Delbrück Centre in Berlin and the ISAR Bioscience Institute in Munich Planegg now demonstrate the processes behind these varying effects. The research team’s findings have been published in the journal ‘Proceedings of the National Academy of Sciences’ (USA).
Fluorescent ligands and new microscopy methods
‘By using molecular design studies that use high-resolution crystal structures of beta adrenergic receptors and stereo-specific synthesis reactions, Dr. Jürgen Einsiedel was able to develop the fluorescent ligand JE1319 in my laboratory. Binding an image producing molecule (fluorophore) with a compound (pharmacophore) in such a way that it generates a specific probe for the receptor was particularly challenging. JE1319 has been used successfully at the University of Würzburg with highly-sensitive and newly established methods in microscopy in order to show the location of beta1 and beta2 adrenergic receptors on cardiac muscle cells,’ explains Prof. Peter Gmeiner from the Chair of Pharmaceutical Chemistry at FAU.
The researchers discovered that beta1 receptors are located all over the surface of cardiac muscle cells, but beta2 receptors are only located on what is known as T-tubules. ‘The specific and special location of the beta2 receptors explains why they do not perform as many functions as beta1 receptors and are limited to direct and short-term stimulation of the heart,’ explains Prof. Martin Lohse from the Institute of Pharmacology and Toxicology at Julius-Maximilians-Universität Würzburg. This stimulation is facilitated by signals that are limited to the cell membranes. In contrast, genes are activated and cell growth is stimulated via far-reaching signals that can only be triggered on the cell surface, where only beta1 receptors are found. Another surprising finding of the research is that not all cardiac muscle cells possess these receptors, which means that not all cells react to adrenaline. The assumption up to now was that the cardiac muscle cells in the large ventricle are all the same.
New approach for treatment of cardiac insufficiency
Patients of chronic cardiac insufficiency have so much adrenaline and noradrenaline in their blood and the heart is stimulated to such an extent that it changes and its cells grow. This counterbalances the cardiac insufficiency in the beginning, but in the long term, this excessive growth damages the heart. These new findings now show that beta1 receptors are found on the entire cell surface and thus have a wider range of effects and are more damaging than beta2 receptors.
This new knowledge about the varying localisation and effects of beta1 and beta2 receptors in the heart could potentially be used to improve treatments for chronic cardiac insufficiency. The aim of close collaborations between FAU and the University of Würzburg is to develop substances that can precisely inhibit the harmful growth of the cardiac muscle cells triggered by beta receptors whilst simultaneously activating the positive effects of stimulating the heart.
Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes, Marc Bathe-Peters, Philipp Gmach, Horst-Holger Boltz, Jürgen Einsiedel, Michael Gotthardt, Harald Hübner, Peter Gmeiner, Martin J. Lohse, and Paolo Annibale, Proceedings of the National Academy of Sciences USA, https://doi.org/10.1073/pnas.2101119118