The Structure and Function of the Serotonin 5-HT2C Receptor

5-HT2C has a role in the psychedelic effect. Understanding it is essential for harnessing the full benefits of nature’s chemical cocktails.

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The serotonin 5-HT2C receptor was first cloned by Julius et al. in 1988.1 At the time, they designated the new receptor 5-HT1C. A new nomenclature for serotonin receptors was proposed by Humphrey et al. in 1993. It placed the receptors into families based on the G proteins they used for signaling and similarities in their DNA amino acid sequences.2 For example, about 50% of the DNA sequences of 5-HT2A, 5-HT2B, and 5-HT2C are identical.3

The Structure of the 5-HT2C Receptor

When the Humphrey et al. receptor naming proposal was adopted, 5-HT1C was renamed 5-HT2C because of its similarities to 5-HT2A and 5-HT2B. In a 2012 paper, Seitz et al. describes the similarities between 5-HT2A (considered the primary receptor for psychedelic effects) and 5-HT2C by saying, “These receptors share a high degree of homology, have overlapping pharmacological profiles, and utilize many of the same and richly diverse second messenger signaling systems.” This homology between receptors can make it challenging to design agonist drugs that specifically target 5-HT2C.

The 5-HT2C receptor (5-HT2CR) is a member of the G protein-coupled receptor (GPCR) family.4 Receptors in this family share a characteristic structure consisting of seven protein helices that span the cell membrane (Figure 1). The helices are separated by alternating sections of the receptor that form intracellular and extracellular loops.

Figure 1: Cartoon representation showing 5-HT2CR in complex with the serotonin receptor antagonist ritanserin.5

The Distribution of 5-HT2C Receptors

As shown in Figure 2, mRNA (messenger ribonucleic acid) coding for 5-HT2CR is expressed primarily in the central nervous system, particularly in the basal ganglia of the brain.

Figure 2: The expression of the 5-HT2CR mRNA in various human tissues (top) and the brain (bottom).6 The data are compiled in the Human Protein Atlas and represent expression profiles from a diverse panel of human cell lines. NX = Normalized expression.

What Does 5-HT2CR Do?

One of the many roles of 5-HT2CR is modulating the effects of the neurotransmitter dopamine.7–9 Activation of 5-HT2CR is thought to have an inhibitory influence on dopamine. Since dopamine acts as a reward chemical in the brain, 5-HT2CR is a drug target for therapies for treating drug addiction.10,11 Also, 5-HT2CR may play a part in the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants.12

A 2007 study found that activation of 5-HT2CR in the amygdala was correlated with anxiety in rats.13 These findings revealed an opportunity for targeting drugs to 5-HT2CR for treating anxiety.14,15 Another 2007 study confirmed the involvement of 5-HT2CR in expressing anxiety.16 The authors of this study suggested a possible mechanism involving the modulation of corticotropic-releasing hormone in the brain in response to stress.

5-HT2CR also has a role in the regulation of body weight and obesity. Knockout mice who are lacking the gene for 5-HT2CR become severely obese (they also can experience fatal seizures).17,18 Lorcaserin (aka Belviq™) is a 5-HT2CR agonist drug designed for weight loss. In 2013, the US Drug Enforcement Administration placed it on Schedule IV because of its hallucinogenic properties. Then, in 2020, Lorcaserin was withdrawn from the market because a clinical trial showed an increase in several types of cancers, including pancreatic, colorectal, and lung.

Is 5-HT2CR Involved in the Psychedelic Effect?

Receptor studies using cloned rat 5-HT2CR indicate that psilocin, for example, has a high affinity for 5-HT2CR. Its Ki value at the receptor is 97.3 nM19 (to learn more about receptor affinity data and what it means, see the Psychedelic Science Review article Binding of Psilocin and Psilocybin to Serotonin Receptors). Here are the Ki values at 5-HT2CR for some other psychedelic compounds:

  • Serotonin = 5.8 nM (human)20
  • LSD = 1.1 nM (human)20
  • 5-MeO-DMT = 100 nM (pig)21
  • MDMA = >10,000 nM (rat)22
  • Psilocybin >10,000 nM (rat)19

In his 2016 paper Psychedelics, Dr. David Nichols states,23

All known psychedelics are agonists at both 5-HT2A and 5-HT2C receptors.

Interestingly, he goes on to say,

…higher doses of particular psychedelics may lead to activation of the 5-HT2C receptor, which often functionally opposes the effects of 5-HT2A receptor activation.

An example of this comes from a 2009 study conducted by Halberstadt et al.24 They observed that low doses of the hallucinogenic amphetamine DOI (2,5-dimethoxy-4 iodoamphetamine) increase locomotor activity in mice while higher doses reduce it. They made the same observation with the head twitch response (HTR), a behavior model that indicates the activation of 5-HT2A.

Allosteric modulation may influence the contribution each serotonin receptor makes to the overall effects of psychedelics. The behavior of GPCRs is modulated by many things, including neurotransmitters, hormones, and ions.25 In addition to the impact of these physiological influences, psychedelics may also be modulators of GPCR function resulting in an entourage effect similar to the compounds in cannabis. Multiple active compounds from naturally occurring sources set the stage for the entourage effect playing a critical role in making formulations.

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Doug Fisher
6 months ago

Bright Minds Biosciences is doing some interesting research on 5HT-2C compounds. One of their scientists, Alan Kozikowski is an expert on the structure-activity relationship of 5HT-2C

    References
  1. Julius D, MacDermott AB, Axel R, Jessell TM. Molecular characterization of a functional cDNA encoding the serotonin 1c receptor. Science. 1988;241(4865):558-564. doi:10.1126/science.3399891
  2. Humphrey PPA, Hartig P, Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends in Pharmacological Sciences. 1993;14(6):233-236. doi:10.1016/0165-6147(93)90016-D
  3. Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behavioural Brain Research. 2008;195(1):198-213. doi:10.1016/j.bbr.2008.03.020
  4. Rosenbaum DM, Rasmussen SGF, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature. 2009;459:356-363. doi:10.1038/nature08144
  5. Peng Y, McCorvy JD, Harpsøe K, et al. 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell. 2018;172(4):719-730.e14. doi:10.1016/j.cell.2018.01.001
  6. Thul PJ, Åkesson L, Wiking M, et al. A subcellular map of the human proteome. Science. 2017;356(6340). doi:10.1126/science.aal3321
  7. Bubar MJ, Cunningham KA. Distribution of serotonin 5-HT2C receptors in the ventral tegmental area. Neuroscience. 2007;146(1):286-297. doi:10.1016/j.neuroscience.2006.12.07
  8. Gobert A, Rivet J-M, Lejeune F, et al. Serotonin2C receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: A combined dialysis and electrophysiological analysis in the rat. Synapse. 2000;36(3):205-221. doi:10.1002/(SICI)1098-2396(20000601)36:3<205::AID-SYN5>3.0.CO;2-D
  9. Di Giovanni G, Matteo VD, Mascio MD, Esposito E. Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin2C/2B receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse. 2000;35(1):53-61. doi:10.1002/(SICI)1098-2396(200001)35:1<53::AID-SYN7>3.0.CO;2-2
  10. Müller CP, Carey RJ. Intracellular 5-HT2C-receptor dephosphorylation: a new target for treating drug addiction. Trends in Pharmacological Sciences. 2006;27(9):455-458. doi:10.1016/j.tips.2006.07.003
  11. Bubar MJ, Cunningham KA. Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem. 2006;6(18):1971-1985. doi:10.2174/156802606778522131
  12. Cremers TIFH, Rea K, Bosker FJ, et al. Augmentation of SSRI Effects on Serotonin by 5-HT 2C Antagonists: Mechanistic Studies. Neuropsychopharmacology. 2007;32(7):1550-1557. doi:10.1038/sj.npp.1301287
  13. Hackler EA, Turner GH, Gresch PJ, et al. 5-Hydroxytryptamine2C Receptor Contribution to m-Chlorophenylpiperazine and N-Methyl-β-carboline-3-carboxamide-Induced Anxiety-Like Behavior and Limbic Brain Activation. J Pharmacol Exp Ther. 2007;320(3):1023-1029. doi:10.1124/jpet.106.113357
  14. Kuznetsova EG, Amstislavskaya TG, Shefer EA, Popova NK. Effect of 5-HT2C receptor antagonist RS 102221 on mouse behavior. Bull Exp Biol Med. 2006;142(1):76-79. doi:10.1007/s10517-006-0296-8
  15. Harada K, Aota M, Inoue T, et al. Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: A comparison with diazepam and buspirone. European Journal of Pharmacology. 2006;553(1):171-184. doi:10.1016/j.ejphar.2006.09.042
  16. Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH. Serotonin 5-HT2C receptors regulate anxiety-like behavior. Genes, Brain and Behavior. 2007;6(5):491-496. doi:10.1111/j.1601-183X.2007.00316.x
  17. Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT 2C serotonin receptors. Nature. 1995;374(6522):542-546. doi:10.1038/374542a0
  18. Tecott LH, Abdallah L. Mouse Genetic Approaches to Feeding Regulation: Serotonin 5-HT2C Receptor Mutant Mice. CNS Spectrums. 2003;8(8):578-588. doi:10.1017/S109285290001885X
  19. Besnard J, Ruda GF, Setola V, et al. Automated design of ligands to polypharmacological profiles. Nature. 2012;492(7428):215-220. doi:10.1038/nature11691
  20. Knight AR, Misra A, Quirk K, et al. Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004;370(2):114-123. doi:10.1007/s00210-004-0951-4
  21. Hoyer D, Waeber C, Schoeffter P, Palacios JM, Dravid A. 5-HT1C receptor-mediated stimulation of inositol phosphate production in pig choroid plexus. Naunyn-Schmiedeberg’s Arch Pharmacol. 1989;339(3):252-258. doi:10.1007/BF00173573
  22. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro. Mol Pharmacol. 2003;63(6):1223-1229. doi:10.1124/mol.63.6.1223
  23. Nichols DE. Psychedelics. Pharmacological Reviews. 2016;68(2):264-355. doi:10.1124/pr.115.011478
  24. Halberstadt AL, Van Der Heijden I, Ruderman MA, et al. 5-HT 2A and 5-HT 2C receptors exert opposing effects on locomotor activity in mice. Neuropsychopharmacology. 2009;34(8):1958-1967.
  25. Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009;8(1):41-54. doi:10.1038/nrd2760