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DavidsonX – D001x – Medicinal Chemistry
Chapter 5 – Receptors
Part 1 – Types of Receptors
Video Clip – Receptor Superfamilies
Receptors are protein switches that control biochemical processes in a cell. The switches
are turned on through the binding of molecules called ligands. Much as a substrate binds an
enzyme to trigger a reaction, a ligand reversibly attaches to a binding site on a receptor
protein to activate a cellular signal process. Ligands themselves can be divided into two
categories: endogenous and exogenous. Endogenous ligands are the natural ligands found
in the body that bind a receptor. Exogenous are unnatural compounds, often drugs, that bind
a receptor.
Receptors are classed into superfamilies, of which there are four: ligand-gated ion channels,
G-protein-coupled receptors, tyrosine kinase-linked receptors, and nuclear receptors.
Ligand-gated ion channels (LGICs) are large receptor proteins that span a cell membrane.
When the proper ligand binds an ion channel, the channel opens and ions of the type
specified by the channel are allowed to pass across the cell membrane and the cell
membrane undergoes depolarization. Ligands that bind an ion channel and cause
depolarization are often neurotransmitters and act upon neurons. In the case of ion channels,
the ligand-binding event leads directly to depolarization. Neurotransmitters that act on ion
channels are therefore called fast neurotransmitters.
G-Protein-coupled receptors (GPCRs) are also cell membrane-spanning receptor proteins,
but GPCRs do not form a channel across the membrane. GPCRs instead provide a means of
communication across the membrane. When a ligand binds on the extracellular side of a
GPCR, the conformation of the receptor protein changes on the intracellular side of the
GPCR. The conformation change causes the release of bound proteins into the cytosol.
These released proteins transmit the signal of the ligand and ultimate cause a cellular change
through a series of steps. Because the ligand binding event is so distant from the eventual
cellular response, neurotransmitters that act on GPCRs are called slow neurotransmitters.
Note that not all GPCRs are neurotransmitters.
Tyrosine kinase-linked receptors (TKLRs) also span the cell membrane. The binding of a
ligand on the extracellular side of a TKLR causes two TLKRs to combine into a dimer,
supramolecular complex of two proteins. Key amino acids (tyrosines) in the complex are
phosphorylated, and the entire complex becomes able to bind key proteins on the intracellular
side of the receptor. The key proteins then propagate the extracellular ligand signal into the
cell. TKLRs are associated with many growth factors and, therefore, with many cancer
pathways when cellular regulation fails.
Nuclear receptors are not bound to the cell membrane and instead are found free in the cell
nucleus. The binding a nuclear receptors impacts many aspects of DNA regulation and gene
expression. The binding of a nuclear receptor by a drug can have broad and difficult to
control consequences within a cell. Nuclear receptor drugs often have a long list of potential
side effects.