New protein find paves way for new heart therapies

A team of scientists has revealed the surprising features on an enigmatic protein. The findings uncover potential new paths to drugs for numerous chronic illnesses.

Scientists have determined unexpected characteristics of a key protein linked to blood pressure control and to nerve growth, pain control and heart tissue regeneration. The findings open doors to potential new therapies to control cardiovascular disease and pain.

The protein, called AT2, is one of a group of receptors that interact with the angiotensin II hormone, which regulates blood pressure. Angiotensin II receptor proteins are important factors in diabetes, hypertension, heart attack and congestive heart failure, and stroke.

AT2 is also a member of a superfamily of proteins called G protein-coupled receptors, or GPCRs. These receptor proteins span the cell membrane, responding to different stimuli outside the cell -- nutrients, hormones and even light -- then triggering responses inside the cell.

Because they are active in so many physiological processes in both healthy and disease states, GPCRs like AT2 are important drug targets.

"AT2's activity has been observed on the organ and organism level, but how it works on the molecular level is not understood," said researcher Vadim Cherezov.

That's in part because AT2 doesn't behave like other GPCRs, according to Cherezov and researcher Vsevolod Katritch.

"AT2 does not work through canonical signaling pathways for GPCRs," Katritch said. "It doesn't activate a G protein and it doesn't work through arrestins."

In most cases, G proteins and a group of proteins called arrestins interact with a cleft that opens up on the intracellular side of GPCRs upon activation. When a stimulus triggers the GPCR from outside the cell, the GPCR activates a G protein or arrestin within the cell, which then relays the signal to other proteins in the cell, and so on, in something akin to a game of molecular "telephone."

While noting that further research is needed, Cherezov said the current discovery is an important first step both to better understanding of similar atypical GPCRs and to potential new therapies.

The study is published online in the journal Nature.