Experimenting With LSD, Scientists Decipher Two Serotonin Receptors

Two receptor molecules for the natural neurotransmitter serotonin, representing a crucial messaging mechanism in our brain that influences our conciousness, have now been deciphered by researchers employing X-ray crystallography to analyze the compounds at an atomic level. This revealed the molecular structures of the two receptors, which hold the key to regulate activities such as sleep, appetite and mood, Nature News reports.

Knowing the exact mechanism and how to activate these receptors would provide targets for future drugs to combat depression, migraines or obesity. They could also help in understanding how the physical structures of the brain produce consciousness.

Bryan Roth, a neuropharmacologist at the University of North Carolina Chapel Hill Medical School, and a co-author of two studies about their findings published in Science last week, explained the relevance and methods.

The analyzed receptors, called 1B and 2B, are just two of the 14 different known serotonin receptors. These molecules lie on the outer membranes of nerve cells; when drugs or neurotransmitters lock into the receptors from outside the cell, they trigger the release of other chemicals inside the cell, so called signalling cascades.

These cascades have different outcomes depending on what drug or neurotransmitter has triggered them, and they activate further hormones and metabolites, which are ultimately responsible for many aspects of the way we feel, perceive and behave.

Scientists have been trying to decipher these serotonin receptors for years. Roth and his colleagues made their breakthrough in uncovering the receptor structures by using X-ray crystallography, in which X-ray beams are fired at crystals of the compound, and the structure is deduced from how the beams scatter.

The scientists then investigated how the found differences in binding between the two receptors affected chemical cascades. They triggered both 1B and 2B with the powerful psychedelic drug LSD and one of its precursors, a migraine drug called ergotamine. The drugs produced two different chemical cascades - G-protein and β-arrestin - from the 1B receptor, but only one (β-arrestin) from the 2B receptor.

Roth says that learning to control the cascades is likely to be crucial in maximizing beneficial effects of drugs and minimizing side effects.

Study:

Chong Wang et al., Structural Basis for Molecular Recognition at Serotonin Receptors, Science, 2013, DOI: 10.1126/science.1232807 Daniel Wacker et al., Structural Features for Functional Selectivity at Serotonin Receptors, Science, 2013, DOI: 10.1126/science.1232808