Researchers have obtained powerful new insights into mechanisms involved in a class of ubiquitous cellular receptors whose signaling functions are implicated in many psychiatric disorders.

The receptors, called G Protein-Coupled Receptors (GPCRs), are the target of one-third of all approved drugs, including therapeutics prescribed for psychiatric disorders including schizophrenia, bipolar disorder, and depression. The dopamine D2 receptor, which is the target of all current antipsychotic medicines, is a GPCR, for example.

The human genome encodes about 800 different GPCRs, which are found in cells throughout the body and are involved in regulating many of the body’s functions. They are found throughout the brain and engage with a variety of neurotransmitters, hormones, and other molecules.

A neurotransmitter (or drug) from outside the cell that binds and activates a GPCR is called an agonist: its docking within the receptor sets off a cascade of events that lead the receptor to engage with and activate G-proteins located inside the cell. G-proteins carry signals that can switch on or off a variety of cellular processes. In this sense, the GPCR can be thought of as a structure that transmits signals from outside the cell to the cell’s interior.

A complex biochemical process is initiated when the moment arrives for a G-protein signal to cease or be diminished in intensity. At the center of this process is a protein called beta-arrestin. The new research explains in unprecedented detail how beta-arrestin is able to halt or modulate GPCR signaling. This provides insight into ways to potentially improve the action of drugs that interact with GPCRs, including psychiatric drugs, to make them more effective and/or to reduce side effects.

Wesley B. Asher, Ph.D., whose 2014 BBRF Young Investigator grant addressed the way beta-arrestin interacts with cellular receptors to modify their signaling, was one of three co-first authors of a paper just published in the journal Cell, describing beta-arrestin—GPCR interactions. The other co-first authors were Daniel S. Terry, Ph.D., and G. Glenn Gregorio, Ph.D. The team’s senior members were Scott C. Blanchard, Ph.D., and Jonathan A. Javitch, M.D., Ph.D., a member of BBRF’s Scientific Council, and a 2010 BBRF Distinguished Investigator, 2003 Independent Investigator, and 1992 and 1990 Young Investigator.

The team used a new technology called smFRET (single-molecule fluorescence resonance energy transfer) to resolve events at the level of individual molecules that help explain the beta-arrestin—GPCR interaction and activation mechanism.

The researchers knew that the interaction begins when part of the GPCR structure, referred to as its “tail”, lying below the cell surface, is phosphorylated. This means that molecules bearing phosphorous—called phosphate groups—are added to the receptor tail. It was also known that the phosphorylated receptor tail in turn binds to a groove on the surface of the beta-arrestin protein. When beta-arrestin is not engaged with a GPCR, however, this groove on its surface is occupied by beta-arrestin’s own tail structure.

The team's research with smFRET imaging reveals how beta-arrestin’s tail gets released to make way for binding the phosphorylated tail of the GPCR. All of these changes can be thought of as changes in shape—"conformational changes” in the beta-arrestin—GPCR complex.

The team’s research showed that when not engaged with a GPCR, beta-arrestin exists in a very stable state that they call “autoinhibited”—and it remains so as long as its own tail structure is tightly bound to the groove in its surface. Beta-arrestin will remain in this stable state unless an agonist like a drug or neurotransmitter interacts with the GPCR from outside the cell.

The research demonstrates how the balance between the autoinhibited and activated states of beta-arrestin controls the intensity and duration of GPCR signaling. Systematic studies tweaking this balance could lead to improved drug therapies or even new drug designs for a variety of illnesses.

"Now that we know GPCR receptors can both activate G-proteins and mediate signaling through beta-arrestin, the hope is that we can develop more specific drug therapies by finding small molecules that preferentially activate one pathway or the other," Dr. Javitch commented.