Homo sapien 5-HT2B
Serotonin Receptor Bound to LSD
Kai Wilczewski-Shirai '21 and Charles Adams '21
Contents:
I. Introduction
The 5-HT2B receptor is a subtype of the general
5-hydroxytryptamine (5-HT2) g-protein associated receptor family that
binds the neurotransmitter serotonin. These receptors are found in the
cardiovascular system, the gastrointestinal tract, and the central
nervous system (CNS) where they mediate functions in the presence of
serotonin. Some cardiovascular effects of 5-HT2B activation are
regulation of cardiac structure, contraction of blood vessels, and the
determination of platelet shape. 5-HT2B (unlike other members of the
5-HT2 family) stimulation in the CNS have been shown to decrease
neuron activity, which plays a role in drug reinforcement, stress,
anxiety, appetite, sleep-wake cycles, and mood regulation.
Overstimulation of these receptors have been shown to lead to abnormal
response to stimuli and hallucinogenic effects in humans. Lysergic
acid diethylamide (LSD) is an agonist for this receptor and is a
substance that can lead to this overstimulation. What makes this
receptor intertesting is the lid binding element, which is responsible
for slow LSD release from the receptor. This lid binding element
allows LSD to bind for long amounts of time, dramatically increasing
the affects of the receptor, compared to other ligands that can bind
to the receptor.
II. Ligands
5-HT2B is a G-protein coupled receptor. It consists of the
typical GPCR seven-transmembrane alpha-helix domain structure. Once
activated, 5-HT2B releases a g-protein (not shown) that triggers a
pathway that upregulates some genes while down regulating others. It
is probable that 5-HT2B activation results in the creation of an
activator or transcription factor for genes that cause
hallucinogenic effects and/or a repressor for genes that prevent
these symptoms when expressed.
is one ligand that can bind to this receptor. While sharing
structural features with
, LSD is much larger than the neurotransmitter and, thus,
will interact differently with 5-HT2B than the normal, endogenous
ligand. The GCPR also binds to many other ligands, including
ergotamine.
III. Binding Pocket
The
, where a ligand binds (in this case, LSD), occupies the
extracellular portions of transmembranes (TM) III, V, and VI. There
are several
in the binding pocket that interact with LSD in different
ways. For example, the ligand makes a hydrogen bond with multiple
residues, including
. This residue interacts with the charged amine portion of
the ligand and forms a stable salt bridge. Other residues that make
hydrogen bonds are Thr140 and Gly221, both of which act as
. Other interactions between the 5-HT2B receptor binding
pocket and LSD are hydrophobic. A couple of these contacts
actually help �push� LSD into the aforementioned hydrogen
donor and acceptors; however, there are
that participate in hydrophobic contacts that serve to
prevent a ligand from releasing once it arrives in the pocket.
IV. Lid Element
LSD has a very slow dissociation rate from 5-HT2B (~46
minutes) which means the receptor will remain active for a long
time. This is probably because, due to its size, LSD is bound not
only to the orthosteric binding site of the receptor (where
serotonin normally resides) but also to the extended binding site.
This site occurs when a
(Extracellular Loop 2) that is typically found at the
entrance of the normal binding pocket, forms a
over the LSD. This greatly inhibits the ability of the
ligand to escape. The extended binding site is considered a �lid�
due more to the function than the actual structure. Some of the
lid residues make
with the LSD; however, most of them are merely there to
sterically hold the hydrophobic contact residues in place. While
making hydrophobic contact with the LSD, Leu209 is hypothesized to
also make hydrophobic contact with residues in the surrounding
transmembranes. It is thought that this residue acts as the
�latch� for the lid. When put together the orthosteric and the
extended binding sites and one gets the
for LSD.
V. Future Research
Data clearly suggest that the 5-HT2B receptor plays a hand
in drug abuse. Considering the extremely slow dissociation rate of
LSD from the receptor, it is likely that 5-HT2B is crucial to the
ability of LSD to have its long lasting effect. Studying this
receptor further can lead to breakthroughs in the treatment of
addiction. Another avenue of exploration could be using general
5-HT receptor activation to alleviate the symptoms of depression
and Parkinson�s Disease. Future researchers should account for and
probably study how overactivation of 5-HT2B affects heart health,
as it has been shown that overactivation can lead to cardiac valve
hypertrophy. Figuring out how to deactivate the receptor can help
eliminate this disease. There are multiple avenues for future
study and each can lead to wonderful breakthroughs.
VI. References
Freeman, S. (2018, March 08). How LSD Works.
Retrieved March 30, 2018,
from https://science.howstuffworks.com/lsd6.htm1
Short- and Long-Term Effects of LSD -
Harmful Effects on the Body - Drug-Free World. (n.d.). Retrieved
March 30, 2018, from http://www.drugfreeworld.org/drugfacts
/lsd/the-harmful-effects-of-lsd.html
Smith, J. S., and Rajagopal, S. (2016,
March 16). The beta-arrestins [Scholarly project]. In The
Beta-arrestins: Multifunctional Regulators of G Protein-coupled
Receptors. Retrieved April 29, 2018, from
http://www.jbc.org/content/early/2016/03/16/jbc.R115.713313.full.pdf
Wacker, Daniel, et al. �Crystal Structure
of an LSD-Bound Human Serotonin Receptor.� Cell, 2016, from
https://www.cell.com/cell/fulltext/S0092-8674(16)31749-411
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