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The Structure of Bias at Serotonin Receptors

26 March 2013. Understanding the targets of antipsychotic drugs, particularly G protein-coupled receptors (GPCRs), may be the key to designing better medicines for schizophrenia and other psychiatric disorders. In the world of GPCRs, two paths lead away from receptor activation: one involves the eponymous G protein second messenger cascade, and another “non-canonical” path activates β-arrestin, a protein that spurs a separate chain of command. But ligands for GPCR do not always stimulate both paths equally, and this may depend on slight differences in GPCR structure induced by a ligand, according to a paper published March 21 in Science.

Led by Raymond Stevens of the University of California in San Diego, and Bryan Roth at the University of North Carolina in Chapel Hill, the study reports finding a biased ligand, called ergotamine, for the serotonin 2B (5HT2B) receptor, and capturing the receptor’s crystal structure while bound to ergotamine. A comparison of this structure with that of the 5HT2A receptor published in a companion paper reveals key features likely to contribute to biased signaling.

There has already been significant work on decoding the structural sources of biased signaling, also called “functional selectivity.” In 2008, Marc Caron and colleagues reported that atypical antipsychotics, which block the dopamine 2 (D2) receptor, interfered with both pathways (see SRF related news story). Interestingly, their effects on the G protein pathway were more variable than on the β-arrestin pathway, which suggested that tamping down β-arrestin signaling might be the more important feature behind why they work. In 2011, Bryan Roth and colleagues developed new ligands for D2 receptors that selectively activated the β-arrestin pathway (see SRF related conference story). These had effects in rodents that matched those of antipsychotic drugs, without motor side effects.

The new findings lay bare for the first time the structures contributing to functional selectivity. Though atypical antipsychotics like clozapine target 5HT2A and 5HT1A receptors (Meltzer et al., 2011), and a biased ligand for a 5HT2A receptor has been designed (see SRF related news story), the 5HT2B receptor featured in the new study does not contribute to antipsychotic drug action. The lessons from it, however, could translate to other GPCRs.

Biased toward β-arrestin
First author Daniel Wacker and colleagues began by expressing cloned human 5HT2B and 5HT2A receptors in HEK293 cells in culture. Tracking cAMP production and phospholipase C activation gave a readout of the G protein pathway stimulation of 5HT1B and 5HT2B receptors, respectively, whereas monitoring interactions between β-arrestin and the 5HT receptors measured stimulation of the β-arrestin pathway. The researchers found that when ergotamine bound to 5HT2B receptors, it selectively activated the β-arrestin pathway; however, when bound to 5HT1B receptors, it lost this bias, activating both pathways fairly equally. This bias held true for related molecules, including lysergic acid diethylamide (LSD), which is derived from ergotamine.

This difference gave the researchers an opportunity to dissect the structural basis of functional selectivity. Crystallizing the 5HT2B receptor while bound to ergotamine, and determining its fine structure down to 2.7 Å, revealed a receptor looking very much like the GPCR it is, composed of seven helices spanning the membrane, bundled together. But a careful comparison of it with the 5HT1B structure solved in the companion paper (Wang et al., 2013), also while bound to ergotamine, revealed some key differences. One difference emerged along the base of the ligand binding pocket, where three amino acids form a kind of trigger, so that agonist binding changes their positions and triggers shifts in the positions of the helices. Compared to the 5HT2A receptor, the 5HT2B receptor shared the same position for two of these residues, but diverged for the third.

On the cytoplasmic side of the receptors, the researchers found a difference in the positions of two of the helices—something that alters the accessibility of binding sites for G proteins or β-arrestin. For the 5HT2B receptor, one of these helices held a position associated with β-arrestin signaling, but the other helix only partially conformed to the position associated with G protein signaling. In another part of the protein, a difference in the side chains in “micro-switch” domains was also discovered, with the 5HT2B receptor showing an intact salt bridge between two side chains, and the 5HT1B receptor missing this salt bridge, due to the non-permissive arrangement of its side chains.

Loops and leashes
The researchers noticed a possible explanation for these differences along an extracellular loop connecting two helices in the bundle. For the 5HT2B receptor, a sharp kink was formed at the connection between the extracellular loop and the top of one of the helices. This shortened the distance spanned by the loop, which could essentially put a leash on the range of movement of these helices. Thus, ergotamine binding would seem to stabilize a more restricted conformation of the receptor, and produce a distinct shape associated with β-arrestin signaling.

The findings illustrate the importance of examining the different structures induced by ligand binding, especially between two receptors with different responses to the same ligand. By tracking the microscopic shifts, rotations, and rearrangements induced by a ligand, researchers will usher in more rational drug design.—Michele Solis.

Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC. Structural Features for Functional Selectivity at Serotonin Receptors. Science. 2013 Mar 21. Abstract

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