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A Lid for Every Pot

Crystal Structure of LSD-Bound Serotonin Receptor

The author, Moad Abd el Hay, works on his doctoral thesis at the Pharmacological Institute of the University of Heidelberg

Edited by Jennifer Them and Kristine Mitchell
Published March 2017

Header photo by Krystal Ng on Unsplash

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Lysergic acid diethylamide (LSD) is one of the most potent human psychoactive drugs with active doses starting at 20-30 µg and effects that last 6-15 hours1,2. In addition to its use as a recreational drug over the past 50 years, recent studies have shown its usefulness in treating substance abuse3, cluster headaches4 and anxiety associated with life-threatening conditions5. Due to the promising results of these studies, there has been an increased interest in understanding the way LSD functions both pharmacologically and in a more broad and general way. Over the past decade, research through neuroimaging methods has added considerably to the knowledge about the effects of LSD in the brain6.

Pharmacologically seen, LSD binds to a wide range of receptors. Its strongest binding affinity is towards the serotonin receptors and its major effects are attributed to its binding to the 5-HT2A receptor. There are two main kinds of receptors that bind neurotransmitters in the human body; the ionotropic receptor and the metabotropic receptor. Upon binding of a substance, the ionotropic receptor opens a pore which allows ions to flow into the cell, thereby activating the cell. Metabotropic receptors, when bound, lead to the activation of one or several signalling pathways in the cell that spread throughout the cells in a domino-like fashion.

5-HT2A is a metabotropic receptor that, depending on which substance it binds, can activate several signalling pathways with varying strengths. Serotonin for example, activates both the Gq pathway and the β-Arrestin pathway. In comparison, LSD activates the β-Arrestin pathway with a much stronger extent. Another peculiarity of LSD is its very long-lasting effect. This has been attributed to its strong binding to the 5-HT2A receptor.

In a study that was published early this year in the journal Cell, Wacker et al. analysed the crystal structure of LSD bound to the 5-HT2B receptor (which is very similar to 5-HT2A)7. From the analysis of the structure they were able to describe the exact binding location of LSD to the receptor. Additionally, when comparing the binding of ergotamine (a non-psychoactive serotonin receptor agonist) to the binding of LSD, they found that the receptor forms a “lid” that covers LSD when it is bound and thereby reduces the chance of it leaving the receptor.

They hypothesized that the lid is responsible for the strong binding of LSD. Through a series of experiments in which the “lid” closing was inhibited, they were able to confirm their hypothesis and even showed that the prolonged binding also explains the strong activation of the β-Arresin pathway in comparison to serotonin.

Through their study they were able to give a molecular explanation of the very long-lasting effects of LSD in addition to further understanding the peculiarities of this receptor. With the crystal structure at hand, the binding of additional serotonin receptor agonists and antagonists can be modelled. These studies could shed some light into the differences between psychedelic and non-psychedelic substances. Additionally, the study shows that the research of psychedelic substances seems to become more acceptable, even in higher-level journals such as Cell. An important step for acquiring research funding and changing the public opinion on these tools.

References

1. Greiner, T., Burch, N., & Edelbert, R. (1958). Psychopatholgy and psychophysiology of minimal LSD-25 dosage. Neurol. & Psychiat., (79), 208. http://doi.org/10.1001/archneurpsyc.1958.02340020088016

2. Passie, T., Halpern, J. H., Stichtenoth, D. O., Emrich, H. M., & Hintzen, A. (2008). The Pharmacology of Lysergic Acid Diethylamide: A Review.  [Review]. CNS: Neuroscience & Therapeutics, 14(4), 295–314. http://doi.org/10.1111/j.1755-5949.2008.00059.x

3. Bogenschutz, M. P., & Johnson, M. W. (2015). Classic hallucinogens in the treatment of addictions. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1–9. http://doi.org/10.1016/j.pnpbp.2015.03.002

4. Sewell, R. A., Halpern, J. H., & Pope, H. G. (2006). Response of cluster headache to psilocybin and LSD. Neurology, 66(12), 1920–1922.

5. Gasser, P., Kirchner, K., & Passie, T. (2015). LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects. Journal of Psychopharmacology, 29(1), 57–68. http://doi.org/10.1177/0269881114555249

6. Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., … Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences, 113(17), 201518377. http://doi.org/10.1073/pnas.1518377113

7. Wacker, Wang, McCorvy, Betz, Venkatakrishnan, Levit, Lansu, Schools, Che, Nichols, Shoichet, D. & R. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 168(3), 377–389.

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