Selective activation of the ß2-adrenergic receptor by a ß-arrestin-biased pepducin promotes activation of a ß-arrestin signaling pathway that is cardioprotective. [Jeffrey Benovic, Thomas Jefferson University]
Selective activation of the ß2-adrenergic receptor by a ß-arrestin-biased pepducin promotes activation of a ß-arrestin signaling pathway that is cardioprotective. [Jeffrey Benovic, Thomas Jefferson University]

Experiments with pepducins, peptides derived from receptor molecules, may lead to a new class of drugs for heart disease. Certain pepducins, report scientists based at Thomas Jefferson University, are capable of interacting with β2-adrenergic receptors and altering their signaling in a new way. The pepducins are capable of activating an alternative signaling pathway to promote contractility. With further development, these pepducins, or more refined versions of them, could be used to bolster failing hearts.

“There's much more work to be done before this is ready for patients,” said Thomas Jefferson University’s Jeffrey Benovic, Ph.D. “But this is an excellent example of how a little curiosity in the basic research laboratory can lead to discoveries that have the potential to change the way we treat a very common and very deadly illness.”

Dr. Benovic is the lead author of a paper (“β-Arrestin–Biased Signaling Through the β2-Adrenergic Receptor Promotes Cardiomyocyte Contraction”) that appeared June 27 in the Proceedings of the National Academy of Sciences. The paper focuses on a β-arrestin–biased pepducin of the β2-adrenergic receptor (β2AR). This pepducin is able to induce cardiomyocyte contractility and antiapoptotic signaling to provide a pharmacological template for next-generation cardiovascular pharmaceuticals.

This finding suggests it may be possible to overcome a drawback associated with β-blockers, which are commonly used to treat heart disease. β-blockers work by blocking the β-adrenergic receptors in the heart, saving heart cells from cell death. But β-adrenergic receptors also help keep the heart pumping, a function that this medication also blocks.

Tapping an alternative β-adrenergic pathway could block damage to the heart and also help it keep pumping. Of the β-adrenergic receptors present in the heart, it is the β1-adrenergic receptors that are primarily responsible for the heart's contraction, or pumping action, and that are targeted by traditional β-blockers. Dr. Benovic's lab, however, had developed pepducins that were derived from pieces of the β2-adrenergic receptor, and which, they discovered, could selectively activate the very receptor they came from.

It was while former graduate student Richard Carr, in Dr. Benovic's lab, was characterizing the properties of these pepducins that he noticed that the molecule shared similar characteristics to a common heart-failure medication called carvedilol. They sent the pepducin to their colleague Dr. Douglas Tilley, Ph.D., at Temple University who tested how heart cells responded to the molecule. “He was blown away by what he saw,” said Dr. Benovic.

When Dr. Tilley pulsed the heart cells with the pepducin, the cells started to beat more forcefully. “We didn't expect that this would happen,” said Dr. Benovic. The pepducin they were using was specific for the β2-adrenergic receptor pathway, and didn't have any effect on the β1 receptors. The researchers had demonstrated for the first time that contraction of heart muscle cells could be triggered via the β2-adrenergic receptor, using this novel pepducin.

Through further biochemical analysis, the researchers showed that the pepducin activated the ability of the β2-adrenergic receptor to interact with a secondary signaling molecule called β-arrestin and that it was this interaction that promoted the heart cells to beat. In addition, the pepducin only activated the β2-adrenergic receptor to 40 or 50%. By tinkering with the pepducin molecules, asserted Benovic, “we think we can get full activation.”

“To understand the relative contribution of β-arrestin bias to the efficacy of select β-blockers, a specific β-arrestin–biased pepducin for the β2AR, intracellular loop (ICL)1–9, was used to decouple β-arrestin–biased signaling from occupation of the orthosteric ligand-binding pocket,” wrote the authors of the PNAS article. “With similar efficacy to carvedilol [a β-blocker], ICL1–9 was able to promote β2AR phosphorylation, β-arrestin recruitment, β2AR internalization, and β-arrestin–biased signaling. Interestingly, ICL1–9 was also able to induce β2AR- and β-arrestin–dependent and Ca2+-independent contractility in primary adult murine cardiomyocytes, whereas carvedilol had no efficacy.”

The next steps, noted Dr. Benovic, are to design a better version of the pepducin. In addition, Dr. Benovic and colleagues plan to screen existing small molecules, or drugs, to see if one can mimic the action of the pepducin. They also plan to study the structure of the pepducin and the β2 receptors to gain better insight into the design of more effective pepducin-like molecules.