Receptor loc­a­tion plays a key role in their function

Receptor loc­a­tion plays a key role in their function

A research team led by Prof. Martin Lohse has iden­ti­fied, for the first time, where spe­cial recept­ors are loc­ated on heart muscle cells. The find­ings open up new per­spect­ives for devel­op­ing ther­apies for chronic heart failure.

Beta1- and beta2-adren­er­gic recept­ors in heart muscle cells (car­di­omyo­cytes): In the left cell, beta1-recept­ors are labelled – they can be found both at the cell sur­face (yel­low) and in the internal t-tubules (green). In the right cell, the beta2-recept­ors are labelled– they occur only in the t-tubules (green), but not at the cell sur­face (which is, there­fore, not vis­ible). (Image: 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 adren­aline and norad­ren­aline. They both trig­ger the strongest stim­u­la­tion of the heart rate and pump­ing capa­city that we know of. The two sub­types are highly sim­ilar bio­chem­ic­ally, but dif­fer sub­stan­tially in terms of their func­tional and thera­peutic relevance.

Both receptor types can stim­u­late the heart in the short term, yet when the beta1 receptor is activ­ated over a pro­longed period of time, it has a range of effects that are not seen with beta2. Beta1 can eli­cit a num­ber of per­sist­ent changes and is endowed with the abil­ity to ini­ti­ate -- often det­ri­mental -- growth of the heart muscle cells by activ­at­ing vari­ous genes.
Recent stud­ies by research­ers at the Max Del­brück Cen­ter for Molecu­lar Medi­cine in the Helm­holtz Asso­ci­ation (MDC) in Ber­lin, the Uni­ver­sity of Erlan­gen, and ISAR Bioscience in Munich-Planegg have now shed light on the mech­an­isms behind 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.

Spe­cial lig­ands and new micro­scopy methods
“Using a fluor­es­cent lig­and syn­thes­ized at the Uni­ver­sity of Erlan­gen and novel highly sens­it­ive micro­scopy meth­ods, we were able to show for the first time where these recept­ors are loc­ated on heart muscle cells,” explains Pro­fessor Martin Lohse, Chair­man of ISAR Bioscience. “The endo­gen­ous recept­ors are expressed at rel­at­ively low levels,” explains Dr. Paolo Anni­bale, long-term col­lab­or­ator of Prof. Lohse and co-lead author of the study. “To detect their move­ment, it was neces­sary to use a form of spec­tro­scopy based on the ana­lysis of the signal’s minute fluor­es­cence fluctuations.”

This revealed that beta1 recept­ors are found on the entire sur­face of heart muscle cells, while beta2 recept­ors are exclus­ively found in spe­cific struc­tures in these cells called T-tubules. Through inva­gin­a­tions of the cell sur­face, these tubules cre­ate a pipe-like net­work that runs through the entire interior of heart muscle cells. “One of the research focuses of our team at the 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 and short-term stim­u­la­tion of the heart,” explains Lohse. Such stim­u­la­tion is medi­ated by sig­nals that are loc­ally restric­ted to the cell mem­brane. In con­trast, gene activ­a­tion and cell growth stim­u­la­tion occur via more far-reach­ing sig­nals that can only be triggered at the cell sur­face, where only beta1 recept­ors are located.

Another sur­pris­ing find­ing of 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 heart muscle cells in the large cham­bers were all the same.

New tar­get for heart fail­ure therapy
It has been known for many years that in chronic heart fail­ure, too much adren­aline and norad­ren­aline cir­cu­late in the blood­stream and stim­u­late the heart to such an extent that it causes changes in the heart and its cells to grow. This ini­tially com­pensates for heart fail­ure, but in the long run the excess­ive 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 greater role in pro­du­cing these adverse effects than beta2 recept­ors. Beta1 recept­ors are loc­al­ized on the entire cell sur­face, enabling them to have a more diverse impact than beta2 recept­ors. The new know­ledge about the dif­fer­en­tial loc­al­iz­a­tion and dis­tinct func­tional effects of beta1 and beta2 recept­ors in the heart could pos­sibly be exploited to develop bet­ter ther­apies for chronic heart fail­ure. These would select­ively inhibit the harm­ful effects of beta recept­ors (such as heart muscle cell growth), while at the same time activ­at­ing the bene­fi­cial effects (such as stim­u­la­tion of heart function).

Marc Bathe-Peters, Phil­ipp Gmach, Horst-Hol­ger Boltz, Jür­gen Ein­siedel, Michael Got­thardt, Har­ald Hüb­ner, Peter Gmeiner, Martin J. Lohse, Paolo Anni­bale. Visu­al­iz­a­tion of β-adren­er­gic receptor dynam­ics and dif­fer­en­tial loc­al­iz­a­tion in car­di­omyo­cytes. Pro­ceed­ings of the National Academy of Sci­ences, 2021; 118 (23): e2101119118

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