“Biased” G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, double electron-electron resonance spectroscopy is used to probe the changes that ligands induce in the conformational distribution of the angiotensin II type I receptor. New research is showing precisely how the crucial cell surface receptors interact differently with various drugs, giving the researchers hope that they may be able to tailor more specific medications for heart patients.

High blood pressure affects one in three American adults, increasing the risk of heart disease and stroke for about 75 million Americans. The blood vessel constriction is triggered by the interaction of a hormone, angiotensin II, with the angiotensin receptor on the surface of cells in the heart, blood vessels, kidney, adrenal cortex, lungs and brain.

ARBs block angiotensin II's beneficial effects

Blood pressure drugs called angiotensin receptor blockers (ARBs) treat high blood pressure by preventing angiotensin II from binding to its receptor. But in doing so, these drugs also block angiotensin II's beneficial effects, including increases in the heart's strength and performance.

"For a long time, people assumed that these receptors had one 'off state' and one 'on state' like a light switch," said lead author Laura Wingler. "But they aren't light switches; these receptors are more like dials with multiple settings, or states. What's been unclear for the past 10 years is what these receptor states look like and why each state triggers different events inside the cell."

Double electron-electron resonance spectroscopy to map the shape of the receptor

The binding of hormones and drugs to the outside of a receptor causes changes in parts of the receptor which face into the cell. Different hormones and drugs push different "buttons" on a receptor, changing its shape in different ways. The Duke-led study used a sophisticated technique called double electron-electron resonance spectroscopy to map the shape of the receptor when it interacts with different classes of hormones and drugs.

"It's like seeing a silhouette of the receptor—an outline of its shape," Wingler said. The researchers discovered that the receptor assumes four main shapes: one associated with ARBs that turn the receptor completely off, one associated with angiotensin II and drugs that turn the receptor fully on and two associated with the drugs that improve heart function without increasing blood pressure.

Wingler compares this approach to seeing an intricate, three-dimensional statue of the receptor. Importantly, it let them see how one drug interacts with the receptor and what "buttons" it presses to change the shape of the receptor. The researchers hope these latest findings may lead to tailor-made drugs for other GPCRs that could separate desired therapeutic effects from unwanted side effects.

These next-generation opioid receptor drugs relieve pain but are less prone to cause the side effects associated with morphine and fentanyl. "Our papers go way beyond anything which has been done in this field before," Lefkowitz said. "This research is likely to lead to discovery and development of novel types of drugs which can manipulate these receptors' shapes in ways that have not previously been possible."